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Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Contents Will it be possible to prevent or treat ageing?
→ p. 4
Alzheimer’s disease and microtubule motors: what’s the connection?
→ p. 16
Divergent evolution of Crocodylus porosus and Gavialis gangeticus cranial morphology. → p. 33
→ p. 36
The science and politics of rewilding
→ p. 54
The naked mole rat: Ugly little monster or beautiful supermodel… for human diseases?
→ p. 59
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The Importance of Cloud Forest Ecosystems and the Challenges They Face
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Foreword Having had a successful first year since launching MUJBSc, we are proud to bring you the first edition of Volume 2. It has been a fruitful year training and expanding our MUJBSc family. We are extremely grateful to all authors for their submissions and the MUJBSc family for their relentless efforts in improving the quality of our publication. Over the last one year, we have seen how this journal has helped share our scientific knowledge to the community while enhancing our writing and communication skills. With every edition, peer review quality has increased, and new talents have been spotted. We believe, with your continued support and encouragement, MUJBSc will continue to spread scientific love.
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“Real science can be far stranger than science fiction and much more satisfying” – Stephen Hawking (1942-2018)
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Will it be possible to prevent or treat ageing? Hayden Jones
Introduction
As we age, accumulations of cellular and genetic damage result in increases in disease and mortality. Over the past few decades, recent advances in technology have allowed investigations into how changes in genomic stability, telomere attrition, epigenetic alterations, deregulated nutrient sensing and advanced glycation end-products cause ageing. In more recent years, the effect of the IGF-1 and mTOR pathways on these mechanisms has also come into question. However, these mechanisms and how they are regulated are not fully understood. Ageing limits the healthy lifespan of humans but it is not well popularised as a research topic amongst scientists. Instead, the diseases that are a product of ageing are investigated independently. Ageing is the link between them and must be researched thoroughly in order to prevent its effects. Here we describe some of the mechanisms that underpin the ageing process, the effects these have on the human body and discuss the potential to delay or even reverse these effects. Upon full elucidation of the complex mechanisms of ageing, these mechanisms can be targeted therapeutically, allowing humans to live disease-free for longer and with increased longevity.
Ageing has many definitions, but changes in an organism that results in loss or gain of function is a common theme amongst them. These changes can be age-related diseases or the natural development of an organism (Bowen and Atwood, 2004). Some effects of ageing are seen as beneficial whereas others contribute to premature death and a reduction in the quality of life. Humans have been obsessed with the prevention of ageing for a significant time, as shown in Oscar Wilde’s novel from 1890, The Portrait of Dorian Gray, in which the main character does not age, but instead the portrait of himself does. The novel is a work of fiction, but there are examples of metazoans that can reverse the effects of ageing and theoretically become immortal through continual reversal to a juvenile state, such as the formerly known Turritopsis nutricula (Piraino et al., 1996), now reclassified as Turritopsis dohrnii (Miglietta et al., 2007). There have also been instances of animals being rejuvenated by scientists; the cognitive function of old mice restored through young mouse blood (Villeda et al., 2014) and bone fracture repair in middle aged mice improved upon bone marrow transplant from juvenile mice (Xing et al., 2010). Research is being carried out in Universities and businesses in the present day in an attempt to understand the mechanisms of ageing and delay age-related diseases. If age-related diseases can be delayed or even
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Abstract
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Faculty of Biology, Medicine and Health, The University of Manchester, U.K.
The mechanisms of ageing The general cause of ageing is the accumulation of cellular DNA damage
Genomic instability As we age, accumulations of DNA damage can lead to genomic instability, Werner Syndrome is an extreme example of this (Hickson, 2003) (described later). Damage to DNA must be reversed or prevented if ageingrelated pathology is to be inhibited. It has been shown that there are three areas of cellular damage which contribute to ageing and age-related diseases; Nuclear DNA, Mitochondrial DNA, and Nuclear lamins. Mutations in nuclear (Brosh and Bohr, 2002) and mitochondrial DNA repair mechanisms (Kujoth et al., 2005) cause diseases that mimic premature ageing. Also, mutations in nuclear lamins, which act as tethering for chromatin and protein
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Improving the quality of life and extension of healthy lifespan is the main aim of research in this area. Increasing the length of time in “good health” will increase the ability to work and function as an individual, without having to rely on others for support. Ageing has a negative impact on many aspects of the human body that can manifest as physical or cognitive issues. For example, around 46% of 50-54-year-olds have osteoarthritis, and by the time of reaching 85 years old, this percentage increases to 62% (Thomas, Peat and Croft, 2013). Several mechanisms of ageing have been considered to cause all the effects and these effects must be reduced or prevented to delay ageing. However, is increasing healthy lifespan of the population achievable; scientifically, ethically and socioeconomically? This review aims to answer that question and to discuss the ethical considerations when discussing increasing human life and health span.
and an inability to repair these changes leading to senescence (Gems and Partridge, 2013). Prevention or treatment of DNA and cellular damage is essential in the effort to treat the signs and symptoms of ageing and reducing mortality and thus longevity and increasing healthy lifespan. LopezOtin et al., 2013, have suggested mechanisms that cause the ageing process and this review will discuss research regarding them. For a mechanism to be accepted as a cause, it must fulfil three criteria; it should normally appear in the ageing process, stimulation of the mechanism would accelerate ageing, and inhibition would decrease the rate of ageing and promote longevity and delay age-related pathology (Lopez-Otin et al., 2013). This review will discuss some of the mechanisms they suggested along with other mechanisms namely; genomic instability, telomere attrition, epigenetic alterations, deregulated nutrient sensing and advanced glycation endproducts (AGE’s).
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reversed, then it may be possible to extend the healthy life span of humans because ageing is a common risk factor in almost all death causing diseases in later life (Dillin, Gottschling, and Nyström, 2014). These age-related diseases usually present together, indicating that they all share a common cause and therefore the same mechanism can be manipulated to prevent them (Peto and Doll, 1997). This general mechanism is believed to be the accumulation of cellular and DNA damage. It is therefore essential to prevent or reverse this if we are to prevent or reverse ageing (Gems and Partridge, 2013).
complexes involved in genome maintenance (Gonzalez-Suarez et al., 2009), cause similar diseases.
immortality and lack of senescence (Shay and Bacchetti, 1997).
Epigenetic alterations
Deregulated nutrient sensing Insulin-like growth factor 1 (IGF-1) is a protein that is associated with growth and development of various tissues around the body (Yakar et al., 2002). It is mainly produced by hepatocytes in response to growth hormone (GH) and acts on many downstream proteins such as the FOXO family of transcription factors (Lopez-Otin et al., 2013). However, the role of the interaction between IGF-1 and the FOXO’s in ageing have yet to be determined. IGF-1
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Telomeres are the sequences of nucleotides at the end of chromosomes that are many thousands of “TTAGGG” repeats long (Meyne, Ratliff, and Moyzis, 1989). Telomerase, a specialised enzyme that produces telomeres, is active in stem cells and also in most cancers which allow them to survive longer than healthy cells. Telomerase can add these repeats onto the 3’ end of chromosomes because it carries an RNA template to add nucleotides onto the DNA whereas DNA polymerases require the presence of primers. Adding primers to the ends of linear DNA cannot be done by normal DNA polymerases, so telomerase is essential to prevent telomeres from shortening. As humans age, telomeres shorten because normal human DNA polymerases cannot replicate DNA completely due to their 5’ to 3’ replicating ability and telomerase being inactive. Human cells can therefore only divide about 50 times (Hayflick and Moorhead, 1961) until senescence and death of the cell occurs; this is called the Hayflick limit. Telomeres are also bound to a protein complex called Shelterin (de Lange, 2005) which prevents DNA repair mechanisms from recognising the telomeres of chromosome as breaks and rejoining them. It has been shown that normal ageing can be slowed without an increased risk of cancer malignancy in mice by inserting the telomerase gene through viral transduction (Bernardes de Jesus et al., 2012). However, activation of telomerase is a contributing factor to most cancers as they use telomerase to exhibit cellular
Epigenetic alterations are changes in gene expression with no change in the DNA base sequence. The three main epigenetic alterations that occur cumulatively throughout life are histone modifications, DNA methylation reactions and chromatin remodelling. In human physiological ageing, epigenetic modifications promote specialisation and development. However, they can begin to promote cancers and other agerelated diseases over time if they occur incorrectly (Reik, 2007). Undesirable epigenetic alterations, such as hypermethylation of the FHIT tumour suppressor gene, can lead to disease (Kvasha et al., 2008). Histone modifications are carried out by the Sirtuin family of enzymes. These are NAD-dependent protein deacetylases and ADP-ribosyltransferases which are a target for prevention of ageing (LopezOtin et al., 2013). One member of the family, Sirtuin 6 (SIRT6), has been shown to extend the life span of male transgenic mice when it was overexpressed (Kanfi et al., 2012).
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Telomere attrition
Advanced glycation end-products (AGEs) AGEs are formed when amino groups react with reducing sugars such as glucose (Cho et al., 2007). They were initially only thought to occur under intense heat as seen in frying of foods but in the 1970’s it was discovered they can be formed in vivo, albeit very slowly (Trivelli, Ranney and Lai, 1971). Since then, they have been implicated in some of the more disastrous effects of ageing; affecting composition of extracellular matrixes, increasing oxidative stress and stimulating inflammation (Semba, Nicklett and Ferrucci, 2010). AGE’s accumulate throughout life and cross link collagen and other proteins in extracellular matrixes, increasing rigidity. This is especially problematic in tissues that are required to be flexible to function such as muscles, tendons and blood vessels. Reduced elasticity in blood vessels leads to higher systolic blood pressure (Greenwald, 2007) and therefore increased risk of death from cardiovascular disease (Gu et al., 2008). In addition to the increased stiffness of tissues, AGE’s can stimulate inflammation by acting as a ligand to the receptor for advanced glycation endproducts (RAGE). AGE binding to RAGE
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The TOR (Target of Rapamycin) pathway is also involved in ageing. However, it is still poorly understood. The mammalian TOR protein, mTOR, is a phosphatidylinositol three kinaserelated kinase that is heavily conserved amongst all known eukaryotic species to date (Xu, Cai and Wei, 2014). mTOR exists as part of two protein complexes, mTORC1 and mTORC2, that regulate
metabolic activity (Laplante and Sabatini, 2012). mTORC1 is especially interesting as it has been shown that inhibition using rapamycin will increase the lifespan of mice by 14% for females and 9% for males (Harrison et al., 2009). mTORC1 can phosphorylate 4E binding proteins (4E-BP) which usually inhibit translation. This results in reduced affinity of 4E-BP’s for the eukaryotic translation initiation factor 4E (eIF4E) so translation can progress, and proteins can be synthesised (Martelli et al., 2011).
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exists in vivo bonded to a group of binding proteins (IGFBP1 to IGFBP6) and an acid labile subunit (ALS) that prevents its degradation and allows it to function (Yakar et al., 2002). IGF-1 circulates in the blood stream and binds to the Insulin-like growth factor 1 receptor (IGF1R) which is present in most cell types. The IGF1R is a receptor tyrosine kinase and will autophosphorylate upon ligand binding, promoting further activation of downstream effectors leading to ageing and development. During investigations into the effect of IGF-1 and ALS deficiencies, ALS knockout and liver IGF-1 deficient mice showed a ~30% decrease in body weight and a 26% decrease in cortical bone volume. These findings are similar to changes that occur in humans during old age as over time, IGF-1 concentrations decrease, and disease prevalence increases. For example, there are significant links between low IGF-1 and increased risk of hip fractures among old women (Garnero, Sornay-Rendu and Delmas, 2000). However, evidence for IGF-1 signalling is conflicted as some studies have shown that high protein intake can upregulate IGF-1 as 50-65-year-olds with high protein intake are more likely to die from cancer than their low-protein (Levine et al., 2014) or vegan (McCarty, 1999) counterparts. This indicates that relatively moderate levels of IGF-1 signalling are required for “proper” functioning.
The effects of ageing are widespread throughout the body and are not specific to certain organs or tissues. The bones, muscles and organs are all affected leading to physical and cognitive decline and increased risk of cancer and other diseases. These pathologies can be attributed to the accumulation of extensive unrepaired DNA damage (Moskalev et al., 2012) leading to over activity of some systems (Cohen, 1994). The key to understanding ageing and attempting to prevent it is the study of the diseases that are heavily linked to it. If the mechanisms that underpin these diseases can be understood, then steps can be taken to counteract them and reduce their effects. Some diseases that mimic the ageing process can also be studied and give us further insight into the mechanisms of ageing.
Werner Syndrome: Does it mimic ageing? The study of diseases such as Werner Syndrome can help to understand and explain some effects of normal physiological ageing. Werner Syndrome is a rare autosomal recessive disease which mimics the signs of ageing. It is present in ten out of every million people and is characterised by a lack of
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The symptoms of ageing
growth during adolescence, premature hair loss, increased risk of osteoporosis and a plethora of other symptoms (Thannhauser, 1945). Several other molecular biological markers of premature ageing are present in Werner's Syndrome, namely chromosomal instability and general genome maintenance dysfunction (Hickson, 2003), indicating that the protein product of the wild-type gene has a gene regulatory component that affects all of the problems above (Chang, 2005). Werner Syndrome occurs because of a defect in the WRN gene, which produces a DNA helicase belonging to the RecQ family (Brosh and Bohr, 2002), resulting in loss of function. There are many different defects in the WRN gene, but all of these defects cause premature termination of translation and result in a truncated C-terminus. Without at least the 128 amino acid residues that are present at the C-terminus, the Nuclear Localisation Signal (NLS) for the WRN protein is defective and will not be present in the nucleus where it usually carries out several functions related to DNA metabolism (Matsumoto et al., 1997). WRN protein has been implicated in non-homologous end joining by using its 3’-5’ exonuclease activity in which it produces 5’ overhangs and allows recombination of the ends (Brosh and Bohr, 2002). It is also worth noting that in a study of 435 genes implicated in ageing, 91% show similar expression levels to those in Werner Syndrome (Kyng et al., 2003). This indicates that the pathways leading to the eventual damage are similar in Werner Syndrome and normal physiological ageing. Understanding the role of WRN, the mechanisms of Werner syndrome and why genomic instability increases over time is a key step in trying to prevent ageing.
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increases reactive oxygen species production through activation of NADPH oxidase and will stimulate downstream inflammatory proteins through activation of the transcription factor NF-kappaB (Bierhaus et al., 2001). AGE’s are a cause of ageing due to their demonstrated ability to cause an accumulation of cellular damage through cross linking and stimulation of chronic inflammatory pathways.
Cancer Cancer is a disease that is characterised by abnormal cell proliferation and invasion of these cells into other areas of
Ageing contributes to cancer through the senescence associated secretory phenotype (SASP). SASP occurs when cells are placed under intense internal or external stress, such as telomere shortening, oxidative stress or severe DNA damage (Coppé et al., 2010). Cells with SASP accumulate over human’s life time and show significant changes in protein synthesis and are able to secrete biomolecules that can promote cancer in surrounding cells. For example, senescent endometrial fibroblasts have been shown to secrete IL-1 at higher rates than usual, promoting hyperplastic epithelial growth (Palmieri, Watson and Rinehart, 1999). As described earlier, telomeres shorten as we age. This leads to a limit of times a cell can divide and replicate before senescence occurs. To counteract this, most cancers have an active telomerase
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Osteoarthritis (OA) is an umbrella term for a variety of disorders that result in degradation of joints in the body. It occurs when the rate of joint tissue damage is faster than it can be repaired (Hunter, McDougall and Keefe, 2008). The inflammation and damage to the joints progresses with age, leading to the death of chondrocytes and reduction in shock absorbing extracellular matrix and cartilage. Pro-inflammatory mediator’s, such as interleukin-1 beta (IL-1β) and Tumour necrosis factoralpha (TNFα), are produced in response to cartilage damage and then stimulate the production of Reactive oxygen species (ROS) in mitochondria. ROS production is associated with DNA breaks and stimulation of apoptosis leading to ageing. Therefore, inflammation leads to high levels of IL1β which then ultimately leads to OA (Goekoop et al., 2010). It has also been shown that changes in growth factor response contribute to OA. Under normal circumstances, transforming growth factor-β (TGF-β) activates ALK5 receptors, stimulates the Smad2/3 pathway, and therefore results in matrix synthesis. However, in old chondrocytes, ALK1 receptors are expressed preferentially, leading to activation of the Smad1/5/8 pathway and eventually matrix metallopeptidase 13 (Wang, Rigueur and Lyons, 2014), which breaks down the extracellular matrix. OA is a very complex disease with very intricate mechanisms that need to be understood if it is to be prevented.
the body. It can be caused by multiple factors, including; genetic mutations, epigenetic modification and abnormal cellular signalling. As we age, the prevalence of cancer increases exponentially, due to the accumulation of DNA damage and abhorrent cellular debris. This damage leads to DNA mutations, a reduction in immunological surveying and decreased DNA repair resulting in uncontrolled proliferation (Moskalev et al., 2012). These effects explain why radiation is more likely to cause cancer if exposed in middle age (Shuryak, Sachs and Brenner, 2010). It is due to the increased susceptibility to DNA damage and reduced function of DNA repair mechanisms that occur over time. To prevent the increased risk of cancer there first must be an understanding of the mechanisms involved. Understanding these mechanisms are important because 9095% of cancers are caused by our environment (Anand et al., 2008).
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Osteoarthritis
There are a few chemicals that are currently of interest in trying to prevent or reverse ageing, delaying diseases and increasing the healthy life span. The two main drugs that are under investigation are Metformin and Rapamycin. Metformin, currently an anti-diabetic drug, has been shown to inhibit some previously mentioned mechanisms of ageing. It is thought to act through inhibition of the mitochondrial respiratory complex one. Metformin enters hepatocytes through SLC22A1 Organic transporter 1 and proceeds to enter the mitochondria and inhibit the mitochondrial respiratory complex 1. This leads to reduced ATP which is required for gluconeogenesis so therefore less glucose is synthesised and there is reduced blood glucose concentrations. Due to this, levels of
Metformin is currently being studied in a large-scale Targeting Ageing with Metformin (TAME) study to investigate its effectiveness over long periods of time in reducing some morbidity associated with ageing. Metformin has been shown to reduce the incidence of cancer by 31% and cancer mortality by 34% (Gandini et al., 2014), and also was found to potentially preserve cognitive impairment as subjects aged (Ng et al., 2014). In addition, a 2017 meta-analysis found that diabetic people taking metformin had a lower all round mortality than non-diabetics and diabetics who weren’t taking metformin (Campbell et al., 2017). These effects could be attributed to a reduction in AGE formation due to a reduction in blood glucose concentration. Rapamycin is another drug that has anti-ageing potential. It acts by binding to FKBP12 (Ehninger, Neff and Xie, 2014) which will then inhibit mTORC1. Inhibition of mTORC1 will lead to several effects that are thought to improve longevity including suppression of translation by being unable to phosphorylate 4E-BP, therefore, preventing eIF4E from initiating translation while also removing the inhibitory effects on autophagy (Yu et al., 2010). This will improve removal of damaged cellular components and prevent inappropriate protein synthesis. It has been shown to be able to increase the lifespan of mice by inhibiting the mTOR pathway (Harrison et al., 2009).
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Current strategies
AMP and ADP increase, leading to Adenosine Monophosphate-activated kinase (AMPK) activation. This contributes to inhibition of lipogenesis, stimulation of fatty acid oxidation and insulin sensitizing effects (Foretz et al., 2014).
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enzyme to prevent shortening and exhibit cellular immortality (Shay and Bacchetti, 1997), but there is another way in which around ~10% of cancers can also prevent shortening without the active telomerase (Cesare and Reddel, 2010): alternative lengthening of telomeres (ALT). ALT is a method that relies on homologous recombination of telomeres of different chromosomes (Dunham et al., 2000). There is strong evidence to suggest cumulative DNA damage resulting in loss of function mutations in two proteins, ATRX and DAXX, leads to the ALT phenotype (Heaphy et al., 2011). However, the role of ATRX and DAXX in ALT is not fully understood but evidence has suggested it is a complicated mechanism involving DNA damage at telomeres, loss of function of ATRX and DAXX and inhibition of telomerase (Hu et al., 2016).
Conclusions Human ageing is a complicated process involving many biochemical pathways that all interact with each other. Investigations of these pathways, through the use of animal models and large-scale studies such as TAME, have shown us that deregulation or damage of these mechanisms leads to ageing. Research discussed in this review have shown that prevention or reversal the mechanisms of ageing can increase healthy lifespan and delay osteoarthritis, cancers and other such age-related diseases from surfacing. It must be decided whether discussing the possibility of extending human lifespan is worth the time and money. The negative effects of ageing contribute to human ill health, suffering and
Understanding the key mechanisms of ageing is essential in trying to prevent the problems that it causes. Study of the mechanisms behind ageing have provided an essential framework for further investigations, and already, several animal studies discussed in this review have shown that the mechanisms of ageing can be manipulated experimentally to improve healthy lifespan, prevent disease and increase longevity. Current studies have shown some theoretical applications with potential to be used on humans in further research, some of these interesting studies are inserting active telomerase using vectors (Bernardes de Jesus et al., 2012) and the overexpression of SIRT6 (Kanfi et al., 2012). However, these have only provided insight into the mechanisms of ageing and further investigation is needed into how these mechanisms could be manipulated to provide useful results over longer periods of time and in humans. Currently, there are two drugs that are approved for other uses that are currently being investigated for their age-related disease prevention potential; Metformin and Rapamycin. Metformin is an anti-diabetic drug that inhibits the mitochondrial respiratory complex 1, leading to alterations in AMP: ATP ratio which will cause activation AMPK leading to activation of TSC2 and subsequent inhibition of mTORC1 (Foretz et al., 2014). Rapamycin inhibits mTORC1 (Harrison et al., 2009), preventing interactions with many
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A consideration when discussing the possibility of extending human life span is the economic impact on society. According to the Office for National Statistics (ONS), the number of people aged 75+ is due to rise by 89.3% by 2039. This increase will come with a sixfold increase in centenarians. Furthermore, the government spends 46% of all adult health care on ages 65+, which totals around ÂŁ6.7 Billion (Office for National Statistics, 2017). The effect of the changing proportions of the population is measured using the dependency ratio (DR). According to the ONS, the DR was around 300 until 2006 and now is expected to reach 487 by 2037. Meaning, for every 1000 people of working age in the UK, there are around 300 who are not working and are dependent on the remaining 700 of working age, rising to 487 not working by 2037 (Visual.ons.gov.uk, 2017).
ultimately, death. If these diseases can be delayed, then death can also be delayed, and a longer health spans can be expected. However, longer life spans may come with new diseases that we have previously not lived long enough to suffer from.
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Ethical considerations
Anand, P., Kunnumakara, A., Sundaram, C., Harikumar, K., Tharakan, S., Lai, O., Sung, B. and Aggarwal, B. (2008). Cancer is a Preventable Disease that Requires Major Lifestyle Changes. Pharmaceutical Research, 25, 2097-2116. Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A., Ayuso, E., Bosch, F. and Blasco, M. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Molecular Medicine, 4, 691-704. Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P., Chen, J., Hong, M., Luther, T., Henle, T., Kloting, I., Morcos, M., Hofmann, M., Tritschler, H., Weigle, B., Kasper, M., Smith, M., Perry, G., Schmidt, A., Stern, D., Haring, H., Schleicher, E. and Nawroth, P. (2001). Diabetes-Associated Sustained Activation of the Transcription Factor Nuclear FactorB. Diabetes, 50(12),.2792-2808. Bowen, R. and Atwood, C. (2004). Living and Dying for Sex. Gerontology, 50, 265-290.
Brosh, R. and Bohr, V. (2002). Roles of the Werner syndrome protein in pathways required for maintenance of genome stability. Experimental Gerontology, 37, 491506.
Cesare, A. and Reddel, R. (2010). Alternative lengthening of telomeres: models, mechanisms and implications. Nature Reviews Genetics, 11(5),.319-330. Chang, S. (2005). A mouse model of Werner Syndrome: what can it tell us about aging and cancer?. The International Journal of Biochemistry & Cell Biology, 37, 991-999. Cho, S., Roman, G., Yeboah, F. and Konishi, Y. (2007). The Road to Advanced Glycation End Products: A Mechanistic Perspective. Current Medicinal Chemistry, 14(15),.16531671. Cohen, H. (1994). Biology of aging as related to cancer. Cancer, 74, 2092-2100. CoppĂŠ, J., Desprez, P., Krtolica, A. and Campisi, J. (2010). The SenescenceAssociated Secretory Phenotype: The Dark Side of Tumor Suppression. Annual Review of Pathology: Mechanisms of Disease, 5(1),.99-118. de Lange, T. (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes & Development, 19, 21002110. Dillin, A., Gottschling, D. and NystrĂśm, T. (2014). The good and the bad of being connected: the integrons of aging. Current Opinion in Cell Biology, 26,107-112. Dunham, M., Neumann, A., Fasching, C. and Reddel, R. (2000). Telomere maintenance by recombination in human cells. Nature Genetics, 26(4),.447-450. Ehninger, D., Neff, F. and Xie, K. (2014). Longevity, aging and rapamycin. Cellular and Molecular Life Sciences, 71, 4325-4346. Foretz, M., Guigas, B., Bertrand, L., Pollak, M. and Viollet, B. (2014). Metformin: From Mechanisms of Action to Therapies. Cell Metabolism, 20, 953-966.
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References
Campbell, J., Bellman, S., Stephenson, M. and Lisy., K. (2017). Metformin reduces allcause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Research Reviews, 40. 31-44.
Page
downstream effectors, and will suppress protein translation and remove limitations on autophagy (Yu et al., 2010). Both of these early drugs show that research into engineering lengthier healthy life spans is developing, but further research is required into the mechanisms of ageing as significant dangers are present with transferring animal studies to human clinical trials in such complex mechanisms and pathways.
Gems, D. and Partridge, L. (2013). Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts. Annual Review of Physiology, 75, 621-644. Gonzalez-Suarez, I., Redwood, A., Perkins, S., Vermolen, B., Lichtensztejin, D., Grotsky, D., Morgado-Palacin, L., Gapud, E., Sleckman, B., Sullivan, T., Sage, J., Stewart, C., Mai, S. and Gonzalo, S. (2009). Novel roles for A-type lamins in telomere biology and the DNA damage response pathway. The EMBO Journal, 28, 2414-2427. Goekoop, R., Kloppenburg, M., Kroon, H., Frölich, M., Huizinga, T., Westendorp, R. and Gussekloo, J. (2010). Low innate production of interleukin-1β and interleukin-6 is associated with the absence of osteoarthritis in old age. Osteoarthritis and Cartilage, 18, 942-947. Greenwald, S. (2007). Ageing of the conduit arteries. The Journal of Pathology, 211(2),.157-172. Gu, Q., Burt, V., Paulose-Ram, R., Yoon, S. and Gillum, R. (2008). High Blood Pressure and Cardiovascular Disease Mortality Risk Among U.S. Adults: The Third National Health and Nutrition Examination Survey Mortality Follow-up Study. Annals of Epidemiology, 18(4),.302-309. Harrison, D., Strong, R., Sharp, Z., Nelson, J., Astle, C., Flurkey, K., Nadon, N., Wilkinson, J., Frenkel, K., Carter, C., Pahor, M., Javors, M., Fernandez, E. and Miller, R. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460, 392-395. Hayflick, L. and Moorhead, P. (1961). The serial cultivation of human diploid cell strains. Experimental Cell Research, 25, 585-621.
Hickson, I. (2003). RecQ helicases: caretakers of the genome. Nature Reviews Cancer, 3, 169-178. Hu, Y., Shi, G., Zhang, L., Li, F., Jiang, Y., Jiang, S., Ma, W., Zhao, Y., Songyang, Z. and Huang, J. (2016). Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX. Scientific Reports, 6(1). Hunter, D., McDougall, J. and Keefe, F. (2008). The Symptoms of Osteoarthritis and the Genesis of Pain. Rheumatic Disease Clinics of North America, 34(3),.623-643. Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., Bar-Joseph, Z. and Cohen, H. (2012). The sirtuin SIRT6 regulates lifespan in male mice. Nature, 483, 218-221. Kim, J., Xu, M., Xo, R., Mates, A., Wilson, G., Pearsall, A. and Grishko, V. (2010). Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthritis and Cartilage, 18, 424-432. Kujoth, G., Hiona, A., Pugh, T., Someya, S., Panzer, K., Wohlgemuth, S., Hofer, T., Seo, A., Sullivan, R. and Jobling, W. (2005). Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging. Science, 309, 481-484. Kvasha, S., Gordiyuk, V., Kondratov, A., Ugryn, D., Zgonnyk, Y., Rynditch, A. and Vozianov, A. (2008). Hypermethylation of the 5′CpG island of the FHIT gene in clear cell renal carcinomas. Cancer Letters, 265, 250-257. Kyng, K., May, A., Kolvraa, S. and Bohr, V. (2003). Gene expression profiling in Werner syndrome closely resembles that of normal aging. Proceedings of the National Academy of Sciences, 100(21),.12259-12264.
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Garnero, P., Sornay-Rendu, E. and Delmas, P. (2000). Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women. The Lancet, 355, 898-899.
Heaphy, C., de Wilde, R., Jiao, Y., Klein, A., Edil, B., Shi, C., Bettegowda, C., Rodriguez, F., Eberhart, C., Hebbar, S., Offerhaus, G., McLendon, R., Rasheed, B., He, Y., Yan, H., Bigner, D., Oba-Shinjo, S., Marie, S., Riggins, G., Kinzler, K., Vogelstein, B., Hruban, R., Maitra, A., Papadopoulos, N. and Meeker, A. (2011). Altered Telomeres in Tumors with ATRX and DAXX Mutations. Science, 333(6041),.425-425.
Page
Gandini, S., Puntoni, M., HeckmanStoddard, B., Dunn, B., Ford, L., DeCensi, A. and Szabo, E. (2014). Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders. Cancer Prevention Research, 7, 867-885.
Matsumoto, T., Shimamoto, A., Goto, M. and Furuichi, Y. (1997). Impaired nuclear localization of defective DNA helicases in Werner's syndrome. Nature Genetics, 16, 335-336. McCarty, M. (1999). Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity. Medical Hypotheses, 53, 459-485. Meyne, J., Ratliff, R. and Moyzis, R. (1989). Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proceedings of the National Academy of Sciences, 86, 7049-7053. Miglietta, M., Piraino, S., Kubota, S. and Schuchert, P. (2007). Species in the genus Turritopsis (Cnidaria, Hydrozoa): a molecular evaluation. Journal of Zoological Systematics and Evolutionary Research, 45(1),.11-19. Ng, T.P., Feng, L., Yap, K.B., Lee, T.S., Tan, C.H., and Winblad, B. (2014). Long-term metformin usage and cognitive function among older adults with diabetes. J. Alzheimers Dis. 41, 61–68.
Ons.gov.uk. (2017). National Population Projections- Office for National Statistics. [online] Available at: https://www.ons.gov.uk/peoplepopulationand community/populationandmigration/populat ionprojections/bulletins/nationalpopulationp
Palmieri, D., Watson, J. and Rinehart, C. (1999). Age-Related Expression of PEDF/EPC-1 in Human Endometrial Stromal Fibroblasts: Implications for Interactive Senescence. Experimental Cell Research, 247(1). 142-147. Peto, R. and Doll, R. (1997). There is no such thing as aging. BMJ, 315, 1030-1032. Piraino, S., Boero, F., Aeschbach, B. and Schmid, V. (1996). Reversing the life cycle: Medusae transforming into polyps and cell Transdifferentiation in Turritopsis nutricula (Cnidaria, Hydrozoa), Biological Bulletin, 190, 302–312. Reik, W. (2007). Stability and flexibility of epigenetic gene regulation in mammalian development. Nature, 447, 425-432. Semba, R., Nicklett, E. and Ferrucci, L. (2010). Does Accumulation of Advanced Glycation End Products Contribute to the Aging Phenotype?. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 65A(9). 963-975. Shay, J. and Bacchetti, S. (1997). A survey of telomerase activity in human cancer. European Journal of Cancer, 33, 787-791. Strait, J. and Lakatta, E. (2012). AgingAssociated Cardiovascular Changes and Their Relationship to Heart Failure. Heart Failure Clinics, 8, 143-164. Thannhauser, S. (1945). Werner's syndrome (progeria of the adult) and Rothmund's syndrome: Two types of closely related heredofamilial atrophic dermatosis with juvenile cataracts and endocrine features. A critical study with five new cases. Annals of Internal Medicine, 23, 559. Thomas, E., Peat, G. and Croft, P. (2013). Defining and mapping the person with osteoarthritis for population studies and public health. Rheumatology, 53, 338-345.
Trivelli, L., Ranney, H. and Lai, H. (1971). Hemoglobin Components in Patients with Diabetes Mellitus. New England Journal of Medicine, 284(7). 353-357. Villeda, S., Plambeck, K., Middeldorp, J., Castellano, J., Mosher, K., Luo, J., Smith,
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
14
López-Otín, C., Blasco, M., Partridge, L., Serrano, M. and Kroemer, G. (2013). The Hallmarks of Aging. Cell, 153, 1194-1217.
rojections/2015-10-29#older-people [Accessed 10 Mar. 2017].
Page
Levine, M., Suarez, J., Brandhorst, S., Balasubramanian, P., Cheng, C., Madia, F., Fontana, L., Mirisola, M., Guevara-Aguirre, J., Wan, J., Passarino, G., Kennedy, B., Wei, M., Cohen, P., Crimmins, E. and Longo, V. (2014). Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population. Cell Metabolism, 19, 407-417.
L., Bieri, G., Lin, K., Berdnik, D., Wabl, R., Udeochu, J., Wheatley, E., Zou, B., Simmons, D., Xie, X., Longo, F. and WyssCoray, T. (2014). Young blood reverses agerelated impairments in cognitive function and synaptic plasticity in mice. Nature Medicine, 20(6). 659-663. Visual.ons.gov.uk. (2017). The changing UK population |Visual.ONS.[online] Available at: http://visual.ons.gov.uk/uk-perspectives-thechanging-population/ [Accessed 20 Mar. 2017]. Wang, W., Rigueur, D. and Lyons, K. (2014). TGFβ signaling in cartilage development and maintenance. Birth Defects Research Part C: Embryo Today: Reviews, 102(1), 3751.
Xu, S., Cai, Y. and Wei, Y. (2014). mTOR Signaling from Cellular Senescence to Organismal Aging. aging and disease, 5, 263-273. Yakar, S., Rosen, C., Beamer, W., AckertBicknell, C., Wu, Y., Liu, J., Ooi, G., Setser, J., Frystyk, J., Boisclair, Y. and LeRoith, D. (2002). Circulating levels of IGF-1 directly regulate bone growth and density. Journal of Clinical Investigation, 110, 771-781. Yu, L., McPhee, C., Zheng, L., Mardones, G., Rong, Y., Peng, J., Mi, N., Zhao, Y., Liu, Z., Wan, F., Hailey, D., Oorschot, V., Klumperman, J., Baehrecke, E. and Lenardo, M. (2010). Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature, 465, 942-946.
Page
15
Xing, Z., Lu, C., Hu, D., Miclau, T. and Marcucio, R. (2010). Rejuvenation of the
inflammatory system stimulates fracture repair in aged mice. Journal of Orthopaedic Research, 28. 1000-1006.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Alzheimer’s disease and microtubule motors: what’s the connection? Gabriella Portlock (gabriella.portlock@student.manchester.ac.uk) Faculty of Biology, Medicine and Health, The University of Manchester, U.K.
42 peptide contribute to the disease and
Abstract
motor defects.
A large body of scientific evidence indicates that dysfunctional kinesin and dynein motors which mediate axonal transport disease
contribute (AD)
transport responsible
is
to
Alzheimer’s
pathogenesis.
Axonal
the
process
for
cellular
movement
of
mitochondria, organelles and proteins to and from a neurone’s cell body. It is an essential cellular process required to maintain the health and strength of the neurone. Axonal transport is mediated
This
paper
reviews
the
current
literature surrounding the relationship between microtubule motors and AD and concludes that there is significant crossover between motor dysfunction and other contributory factors to the disease. In addition, by way of societal context, this paper also indicates how contemporary research in this area is contributing to the identification of potential therapeutic targets towards the treatment of AD.
by molecular motor proteins that carry their cargo along cytoskeletal tracks:
Introduction
microtubules. There are many factors that contribute to motor dysfunction
molecules such as glycogen synthase kinase-3ß. Additionally, although their chronological position in the progression of AD is disputed, it is largely accepted that the microtubule-associated protein tau and accumulations of beta-amyloid-
chronic and progressive dementia that does not have a preceding cause such as stroke or brain trauma (Rang et al, 2015). It is characterised by brain shrinkage cholinergic
and
localised
neurones
loss in
of the
hippocampus and basal forebrain. This causes the loss of short-term memory,
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
16
motor mutations and overactive kinase
Alzheimer’s disease (AD) refers to a
Page
which can then lead to AD, including:
Figure 1: Factors implicated in Alzheimer’s disease pathogenesis and the links between them. Microtubule motor dysfunction is instigated through a variety of pathways and contributes to AD onset through three main factors: accumulation of amyloid precursor protein and its cleavage products; exacerbation of the formation of neurofibrillary tau
tangles; and axonal transport defects that cause the accumulation of synaptic vesicles and mitochondria. These factors then lead to neuronal death which contributes to the memory defects and cognitive dysfunction associated with AD. Blue arrows indicate pathways in which initial motor dysfunction leads to AD onset. Green arrows indicate how certain proteins can cause motor dysfunction through stimulating hyperactivity of kinase molecules glycogen synthase kinase-3ß (GSK-3ß), casein kinase 2 (CK2) and c-Jun NH2-terminal
progressive
present, it has been widely accepted that
cognitive impairment (Rang et al, 2015).
the two common features of AD are
At present, there is no cure for AD that
extracellular beta-amyloid plaques and
stops or reverses its progression, though
neurofibrillary tau tangles (Masters et
some treatments have been developed
al, 2015). Recent studies have suggested
which temporarily improve symptoms
a link between the appearance of these
(WHO, 2016). Part of the reason for the
two AD features and axonal transport
lack of cure is that AD’s mechanisms of
defects within neurones (Spires-Jones
onset are still not fully understood. At
and Hyman, 2014; Khan and Bloom,
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Page
language break down and
17
kinase (JNK). This subsequently leads to AD onset.
2016 and Sherman et al, 2016). Coupled
synapse, where they are used to initiate
together, these lead to axonal swellings,
action
initiating
and
neurones (Vicario-Orri et al., 2015).
are
Axonal transport is an essential process
to
in neurones because of their extreme
axonal transport defects which have
polarity and large size (some axons are
considerable cross talk with each other,
over a metre in length) (Cassimeris et al,
highlighted in Figure 1. In this paper,
2010; Encalada and Goldstein, 2014).
theories
neuronal
consequently, multiple
AD
factors
death
onset. that
contribute
neighbouring
of
Axonal transport also clears re-cycled or
will
be
misfolded proteins from the axon to
discussed and their possible connection
avoid the build-up of toxic aggregates.
to
Dysfunction
transport
beta-amyloid
the
in
causes
axonal
surrounding
There
potentials
defects plaques
and
tau
of
this
process
when
neurofibrillary tangles. Finally, to add
clearing beta-amyloid peptides is linked
societal context, the paper also indicates
to the onset of AD (Vicario-Orri et al,
how contemporary research in this area
2015).
is contributing to the identification of potential therapeutic targets towards The movement of cargo along the axon is
undertaken
by
molecular
motor
proteins that move along cytoskeletal tracks in the axon. These cytoskeletal
The neurones’ role in the nervous
tracks are made up of microtubules:
system is to pass sensory and motor
dynamic and polarised tubulin polymers
information along their axons to be
(Cassimeris
transmitted across the synapse to more
microtubules are in a constant state of
distal parts of the brain and spinal
dynamic
column
2015).
continuous changes in length. However,
Neuronal health relies on the transport
the microtubule can be stabilised by
of proteins, mitochondria and other
microtubule-associated proteins (MAPs)
biomolecules from their site of synthesis
such as tau, which is also implicated in
to their site of action via axonal
the progression of AD (Vicario-Orri et
transport (Cassimeris et al., 2010). For
al., 2015). Two major families of motor
example, some neurotransmitters are
protein
made in the cell soma and transported
transport cargoes to their sites of action
(Vicario-Orri
et
al,
et
al.,
instability
have
been
2010). –
The
undergoing
identified
that
in synaptic vesicles down the axon to the
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
18
Axonal transport along microtubules in neurones.
Page
the treatment of AD.
in the neurone: kinesins and dyneins
However, more cumbersome cargoes
(Figure 2) (Cassimeris et al, 2010).
such as neurofilament proteins are
Figure 2: The molecular structure of kinesin-1 and dynein motor proteins. On the
right of the diagram is kinesin-1, which moves via anterograde axonal transport towards the plus end of the microtubule. The main structural chains in the kinesin-1 motor are shown, as is one of the most common kinesin-1 cargo adaptor proteins: JNK-interacting protein (JIP1). On the left is a dynein motor protein - dynein moves in the retrograde direction towards the minus end of the microtubule. The main chains that form dynein are listed, along with the main molecules that make up its associated dynactin activator complex. The general structure of a microtubule inside a neuronal axon is shown. The highly dynamic plus-end of microtubules point towards the axon terminal/synapse, whilst the generally more stable minus-end points towards the cell soma.
in
anterograde
transported
by
slow
anterograde
transport at rates between 0.2-1mm/day (Vicario-Orri
biomolecules,
and
anterograde transport still utilises the
mitochondria by kinesin motors from
kinesin motor protein, but there is an
the cell body to the axon terminal,
increased number of pauses between
usually at fast rates of 200-400mm/day
movements down the microtubule. The
(Millecamps
kinesin microtubule motor superfamily
organelles
and
Julien,
2013).
et
al.,
2015).
Slow
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
19
Anterograde transport is the delivery of
Page
Kinesins transport
(KIFs) includes more than 40 subtypes;
heavy
chains
(DHC),
several
light
however,
chains
(DLC)
which
include
light
their
general
structural
features are defined by the structure of
intermediate chains and intermediate
the most common kinesin – kinesin-1
chains (DIC) (Eschbach and Dupuis,
(Cassimeris et al., 2010). Kinesin-1
2011). The heavy chains bind ATP and
consists of two heavy chains (KHC) and
microtubules, whilst the other chains
two light chains (KLC) depicted in
bind to cargo and dynactin (Cassimeris
Figure 2 (Millecamps and Julien, 2013).
et
Within the KHCs is a globular motor
accepted to be an activator of the dynein
domain
microtubule-
motor, allowing dynein to transport its
binding site and an ATP-binding site.
cargo towards the cell soma at rates of
Kinesins use the hydrolysis of adenosine
150-300mm/day (Wang et al., 2015).
containing
triphosphate
a
(ATP)
to
drive
conformational changes that allow them to generate a motile force to transport cargoes along microtubules (Cassimeris et al, 2010).
al.,
2010).
Dynactin
is
largely
Dysfunction of axonal transport via motor protein defects Evidence suggests that AD pathologies can arise through impeded movement of
Dyneins transport
in
retrograde
the kinesin and dynein motor proteins that mediate axonal transport (Kulić et
The other main type of microtubule
al., 2008). Motor proteins need to
motor
navigate effectively and deliver cargoes
for
dynein,
retrograde
which
is
transport
to
the
correct
locations
without
(Figure 2) (Millecamps and Julien,
encountering any major interferences on
2013).
transport
the microtubule that could cause them
allows neuronal cell bodies to receive
to stop and accumulate. The halting and
information
external
subsequent build-up of motor proteins
environment surrounding their nerve
and their associated cargoes is known as
terminal (Eschbach and Dupuis, 2011).
a ‘traffic jam’ (Encalada and Goldstein,
Another
2014). Within the crowded neuronal
Retrograde
axonal
about
the
important
function
of
retrograde transport is the removal of
axon,
damaged
abundance
proteins
from
the
nerve
motors of
contend soluble
with
an
proteins
and
terminal, such as beta-amyloid protein
organelles which can obstruct their
(Reynolds et al, 2000). Dyneins are a
movement. As the motors accumulate,
multi-subunit complex consisting of two
the axon starts to swell, eventually
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
20
responsible
is
Page
protein
triggering the neurone to initiate either
kinase-3ß (GSK-3ß) and casein kinase 2
apoptosis or necrosis (Encalada and
(CK2) have been implicated as vital
Goldstein, 2014). In AD, this process
regulators of axonal transport (Pigino et
happens in many cholinergic neurones –
al., 2009). Under normal conditions,
contributing to a great loss of cell mass
these kinase molecules control the rate
in the hippocampus and basal forebrain.
of movement of cargo (such as amyloid precursor protein) down the axon by phosphorylating kinesin-1 and dynein
More evidence in favour of a role for
motor proteins (Weaver et al., 2013 and
aberrant
AD
Mudher et al., 2004). GSK-3ß and CK2
pathogenesis came from observations
directly phosphorylate a KLC causing
that mutations in KLC, KHC, DHC and
kinesin-1 to detach from its cargo.
dynactin genes have been shown to
Dynein
cause motor paralysis in Drosophila and
molecules
Caenorhabditis elegans (Arimoto et al.,
subsequently
2011 and Koushika et al., 2004). This
protein, which plays a vital role in
resulted in ectopic accumulation of
dynein
synaptic
Ndel1 reduces its ability to bind to each
axonal
vesicles
transport
and
in
mitochondria,
is
inactivated
via
kinase
phosphorylating
and
disabling
motility.
the
Phosphorylation
leading to neuronal starvation and
DIC,
death
inactivation (Gao et al., 2015).
(Koushika
et
al.,
2004
and
Ndel1
eventually
causing
of
motor
Arimoto et al., 2011). Furthermore, reduced levels of KLC2, KLC1 and DIC motor chains were observed in the
Amyloid precursor protein (APP), its
frontal cortex of AD patients, adding to
cleavage
the mounting evidence that incorrectly
manipulate the activity of GSK-3ß and
formed microtubule motors play a role
CK2 to cause a huge reduction in axonal
in AD onset (Morel et al., 2012).
transport, leading to axonal swellings
phosphorylation of both kinesin and dynein motor proteins represents a major mechanism for the regulation of axonal transport (Wang et al., 2015 and
tau
can
and thus, neuronal death (Wang et al., 2015, Jope and Johnson, 2004 and Lei et al., 2011). Additionally, c-Jun NH2terminal
kinase
(JNK)
is
also
an
important regulator of axonal transport (Verhey et al., 2001). It is activated by the neurone in response to stress signals such as the inflammatory cytokine,
Pigino et al., 2009). Glycogen synthase Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
21
Recent studies have suggested that
and
Page
Kinase regulation of axonal transport
products
tumour necrosis factor alpha (Verhey
formation and neural plasticity (Nguyen
and
blocks
et al., 2008). Within neurones, APP is
by
synthesised in the cell body and then
cause
undergoes anterograde axonal transport
complete motor dissociation from the
via kinesin-1 (Müller and Zheng, 2012).
microtubule (Verhey and Hammond,
Whilst
being
2009). It has also been posited that JNK
cleaved
by
phosphorylation of kinesin-1 contributes
undertaken by cleaving enzyme BACE1)
to a complete shift of axonal transport to
and γ-secretase (a multi-subunit protein
retrograde transport only. This shift
complex including presenilin 1 and
may be to allow the neurone to transport
presenilin
any damaged proteins to the cell soma
peptides 40 and 42 (Wang et al., 2015
to be destroyed before normal transport
and Nguyen et al., 2008). It has been
can be resumed (Cavalli et al., 2005).
suggested
JNK activity can also be manipulated by
activated in the presence of mutated
the
forms of APP and presenilins (Lei et al.,
Hammond,
kinesin-1
based
phosphorylating
transport KHCs
common
to
neuropathological
associated
with
AD:
tau
2011).
transported, ß-secretase
2)
to
that
form
is
(primarily
beta-amyloid
GSK-3ß
This
APP
is
causes
hyper-
increased
neurofibrillary tangles and beta-amyloid
detachment of kinesin-1 from its cargo,
oligomers
leading to reduced axonal transport of
(Verhey
and
Hammond,
2009).
APP and its cleavage products to the
APP and beta-amyloid-42 peptide effects on axonal transport Synaptic dysfunction, cognitive decline and plaque deposition of the betaamyloid
peptide
derived
from
its
precursor protein, ‘APP’, are hallmarks of AD (Müller and Zheng, 2012). APP is an
integral
protein
with
type a
1
transmembrane
large
extracellular
domain and a short cytoplasmic tail. APP is expressed in many tissues but is most concentrated in neuronal synapses, where it is thought to regulate synaptic
axon terminal (Lei et al., 2011 and Szpankowski et al., 2012). Furthermore, mutated APP and presenilins contribute to both increased cleavage of APP and increased formation of pathogenic betaamyloid-42 pathogenic
peptides
over
beta-amyloid-40
nonpeptides
(Terwel et al., 2008 and Gunawardena et al., 2013). Pathogenic beta-amyloid-42 peptide
is
highly
fibrillogenic,
and
reduced axonal transport allows it to build-up and aggregate within the axon to first form beta-amyloid oligomers and then extracellular beta-amyloid plaques (Figure 1) (Wang et al., 2015).
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
22
features
JNK
Page
two
2009).
phosphorylating kinesin-1 and dynein, Although
the
common
neuropathic
feature of AD, beta-amyloid plaques are found extracellularly; it is thought that the production and oligomerisation of beta-amyloid occurs inside membrane compartments
such
as
endosomes,
within the axon (Mokhtar et al., 2013). There is mounting evidence to suggest that soluble beta-amyloid oligomers, rather than plaques, are responsible for synapse
failure
and
early
AD
pathogenesis (Vicario-Orri et al., 2015; Jope and Johnson, 2004). Evidence indicates that fast axonal transport is disrupted by beta-amyloid oligomers and that this effect is dependent on both Nmethyl
D-aspartate
receptors
(NMDARs) and GSK-3ß (Peineau et al., 2007).
NMDARs
and
GSK-3ß
are
functionally related: during long-term potentiation (LTP) when NMDARs are activated, they trigger the PI3K/Akt signal
transduction
pathway
which
phosphorylates and inactivates GSK-3ß to prevent long-term depression (LTD) (Peineau et al., 2007). Beta-amyloid oligomers have been shown to affect NMDAR function by inducing neuronal oxidative stress and hyper-activating
causing kinesin to detach from its cargo and dynein inactivation (Verhey and Hammond, 2009). This leads to a huge reduction in axonal transport, causing a build-up of not only organelles and mitochondria, but also more pathogenic beta-amyloid-42
peptides
that
eventually oligomerise. The mechanisms discussed
above
suggest
that
beta-
amyloid-42 induced hyper-activation of GSK-3ß contributing to a vicious cycle of increased
pathogenic
beta-amyloid
oligomer formation and the blockage of axonal transport (Pigino et al., 2009). The
initial
pathogenic
beta-amyloid
oligomers formed through the blockage of axonal transport, via mutated APP and presenilins, can over-activate more GSK-3ß, which in turn will form more pathogenic oligomers (Figure 1) (Lei et al, 2011). This cycle of beta-amyloid oligomer formation leading to motor dysfunction and inhibition of axonal transport leads to a mass of cell death. This suggests that there is significant cross over between dysfunctional motor proteins
and
amyloid-42
the
pathogenic
peptide
in
betatheir
contributions to AD pathology.
GSK-3ß. Coupled together, these factors
(Peineau et al, 2007). GSK-3ß induces LTD
through
continuously
Impairment of LTP by beta-amyloid oligomers is prevented by inhibitors of CK2, suggesting a possible role for
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
23
breakdown of memory shown in AD
Page
cause increased LTD, leading to the
hyper-activated CK2 in AD pathogenesis
machinery
(Pigino et al., 2009). The mechanism of
motor-based transport. This leads to
inhibition of axonal transport caused by
increased formation of the pathogenic
both GSK-3Ă&#x;
and CK2 is similar,
beta-amyloid-42
involving
phosphorylation
contribute to AD onset. However, a
the
of
a
can
microtubule
oligomers
recent
detachment of kinesin-1 from its cargo
variants of normal motor chains in
(Vicario-Orri et al., 2015). However,
enhancing
some studies have shown that GSK-3Ă&#x;
increasing
more
formation
blocks
anterograde
has
which
kinesin light chain which promotes
often
study
impede
AD
implicated
pathology
beta-amyloid (Morihara
et
splice
through oligomer
al.,
2014).
transport, whereas hyperactivity of CK2
Morihara et al. (2014) identified that
inhibits
transport
directions, profound
equally
in
both
kinesin light chain-1 splice variant E
having
a
more
(KLC1E)
thereby effect
in
the
amount
of
axonal
pathogenic beta-amyloid accumulation
swellings (Pigino et al., 2009, Mudher et
inside rodent brains. In addition, it was
al., 2004 and Gao et al., 2015). Other
recognised
studies have suggested that axonal
expression levels of KLC1E in the brain
transport
by
was significantly higher in AD patients
hyperactivation of JNK (Morfini and
compared with unaffected individuals.
Pigino,
JNK
Conclusively, knockout of KLC1E in
to
cause
rodent brains decreased the production
kinesin-1
from
can
be
2007).
phosphorylates detachment
inhibited
Hyperactive a
KHC
of
microtubules,
causing
increases
leading
to
the
of
that
in
beta-amyloid-42
reducing
both
humans,
peptide,
the
thereby
oligomerisation
and
accumulation of cargoes and axonal
perhaps, the risk of developing AD. This
swelling (Cavalli et al., 2005). Overall,
study shows that AD pathology may be
aberrant
protein
exacerbated by the splicing of essential
kinases on microtubule motor mediated
motor chain KLC1 to form KLC1E. It
axonal transport can severely damage
also demonstrates that the combination
neurones, which may actively contribute
of
to the onset of AD (Morfini and Pigino,
transcriptomics is an efficient approach
2007).
in identifying key genes involved in
activity
of
many
transgenic
animal
models
and
common yet complex diseases (Morihara It has been indicated already that mutations
in
the
APP
cleavage
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
24
`, 2014).
Page
et al.
The MAP tau and its effects on axonal transport
transport (Dixit et al., 2008). This
The stability of microtubules is critical
anterograde
for neuronal function and it is impaired
transport,
in neurodegenerative disorders such as
movement
AD (Encalada and Goldstein, 2014).
(Mandelkow and Mandelkow, 2012).
MAPs play a key role in microtubule
There are, however, reports that tau can
stabilisation and regulation of kinesin
inhibit some dynein-mediated transport:
and dynein mediated transport. Tau is
in mouse retinal ganglion cells high in
an
the
abundant
MAP
with
several
impairment
preferentially
affects
kinesin-dependent with
dynein
mediated
less
affected
being
mutant
Tau
P301S
isoform,
of
dynactin functioned abnormally and
microtubules, neurite outgrowth and
caused ineffective loading of cargoes at
membrane association that depends on
the cell soma (Magnani et al., 2007).
its phosphorylation status (Encalada
Impaired transport in both directions
and Goldstein, 2014). Fibrillary tau
results
deposits, in the form of neurofibrillary
vesicles accumulating within the cell
tangles, are key pathological features of
body, causing neuronal starvation and
AD and tau aggregates are toxic to
eventually death (Dixit et al., 2008).
neurones
Competition between tau and kinesin-1
functions,
including
(Masters
stabilisation
et
al.,
Evidence
2015).
implicates
for
in
the
mitochondria
kinesin-1
and
binding
other
site
on
hyperphosphorylated tau isoforms in
microtubules is a mechanism proposed
neuronal dysfunction (Fox et al, 2011).
for
Tau decorates microtubules, acting as a
transport (Stamer et al., 2002). In
block
it
addition, tau could regulate fast axonal
(Cassimeris et al., 2010). In vitro, upon
transport by alternative mechanisms.
encountering tau, kinesin-1 detaches
For example, tau filaments directly
from
dynein
activate the phosphatase PP1, causing
reverses
the activation of GSK-3Ă&#x; which leads to
movement toward the plus ends of
the detachment of kinesin-1 from its
microtubules (Dixit et al., 2008).
cargo,
to
motors
microtubules,
pauses
and
that
run
whereas
temporarily
into
how
tau
inhibits
leading
to
kinesin-based
axonal
swelling
(LaPointe et al., 2009). Furthermore, phosphorylate more monomeric tau to
hyperphosphorylated tau isoforms in
further
cortical
pathogenic
neurones
inhibit
axonal
increase
the
amount
hyperphosphorylated
of tau
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Page
Studies have reported that high levels of
25
after tau activates GSK-3Ă&#x;, it can
within the neurone (Jones and Hyman,
reported that mice expressing three-fold
2014). The hyperphosphorylated tau
higher than normal levels of human tau
then aggregates to form neurofibrillary
displayed normal fast and slow axonal
tau tangles which build up in the axon,
transport,
causing
The
abnormally hyperphosphorylated tau in
neurofibrillary tau tangles enhance the
their brains (Yuan et al., 2013). This
reduction in axonal transport, again
indicates that axonal transport rates in
indicating GSK-3Ă&#x; in a vicious cycle of
vivo
axonal transport inhibition (Figure 1)
overexpression,
or
(Jones and Hyman, 2014). Notably, tau
pathologically
high
reduction has been reported to enhance
hyperphosphorylated
beta-amyloid oligomer induced defects
insufficient to impair axonal transport
in axonal transport in transgenic mice,
function.
axonal
swelling.
suggesting that there is a connection between tau and beta-amyloid oligomer contribution
to
motor
dysfunction
(Vossel et al., 2010; Khan and Bloom, 2016).
despite
are
the
unaffected
detection
by
of
moderate
possibly
that
levels tau
of
alone
are
Microtubule motors as therapeutic targets for the treatment of AD Axonal transport defects, mediated by microtubule motors, are clearly a key factor in the pathology of AD and thus
The effect of tau on motors is a subject
need
of debate, with some studies showing
development of a treatment for the
that
can
disease. Transport defects in AD arise
inhibit anterograde transport of various
partly from the aberrant activity of the
cargoes, including APP, by blocking the
microtubule
initial attachment of kinesin motor
caused by hyperphosphorylation and
proteins to microtubules and inhibiting
aggregation
kinesin motility (Wang et al., 2015).
neurofibrillary tangles. Studies have
Others have challenged this notion and
shown
have
that
hyperphosphorylated
the
considered
stabilising into
that
in
protein
the
tau,
insoluble
microtubule-stabilising
binding
of
drugs can be used to compensate for the
tau
to
loss of normal tau function and to
microtubules does not directly affect
restore
normal kinesin
kinesin or cytoplasmic dynein-based
function
motility (Yuan et al., 2008; Morfini and
Recently, a microtubule-stabilising drug
Pigino, 2007). Some researchers have
epothilone
(Quraishe D
et
(EpoD),
and
dynein
al.,
2013).
which
can
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
26
shown
tau
be
Page
hyperphosphorylated
to
penetrate the blood-brain barrier and is compensate for dysfunctional tau and
Conclusion – so what is the connection between microtubule motors and AD?
reverse axonal transport disruption in
There is no doubt that impaired function
animal models (Quraishe et al., 2013).
of microtubule motors contributes to the
non-toxic,
has
been
developed
to
severity of AD. However, what is still
motors
that
mediate
transport.
Therefore, the potential strategies to restore axonal transport focus on these motor
proteins.
Phosphorylation
of
kinesin and dynein plays a crucial role in the regulation of cargo movement throughout the neurone. Hyperactivity of protein kinases including GSK-3ß and JNK is observed in AD and thus, targeting kinase activity could be a potential
therapeutic
restoring
axonal
approach
transport
for
function
(Vicario-Orri et al., 2015). For example, JNK hyperactivity causing deficits in microtubule motor activity has been reported in AD and its inhibition in vivo has neuroprotective effects in animal models
(Morfini
Furthermore, examined
et
recent the
way
al., studies
2007). have
proteasome
associated protein Nedd8 induced GSK3ß degradation. This protein could be manipulated to modulate the GSK-3ß hyperactivity that contributes to AD pathology (Agholme et al., 2014 and Del Ser et al., 2013).
onset or the result of it. The evidence proposed in this essay suggests more strongly that neuronal degeneration in AD is likely the result of reduced axonal transport through the dysfunction of motor proteins. Motor dysfunction comes about in a variety of ways, including through
mutations
in
the
motors
themselves which can lead to a depletion in the transport of synaptic vesicles, mitochondria
and
organelles
along
axons. The build-up of mitochondria causes the starvation and subsequent death of neurones in the hippocampus and basal forebrain, leading to AD onset.
Furthermore,
phosphorylation
of
excessive
the
motors
via
kinases such as CK2, JNK and GSK-3ß is strongly linked to AD pathogenesis. Aberrant kinase activity can cause dynein and kinesin to detach from both the
microtubule
and
their
cargoes,
leading to an accumulation of proteins and organelles within the axon. The accumulation of these molecules blocks the
axon,
inhibiting
transport
and
causing axonal swelling, resulting in neuronal apoptosis or necrosis. Mutated
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
27
caused by defects in the molecular
disputed is whether this is causal in AD
Page
Axonal transport dysfunction is mainly
APP
and
its
associated
cleavage
conclude,
although
the
connection
molecules also evidently play a key role
between microtubule motors and AD is
in triggering axonal transport defects
apparent and becoming clearer, further
that
These
research is vital to define the role that
mutated proteins trigger hyperactivity
motors play more clearly in this life
of kinases, and this leads to the
limiting disease. This research will
formation
beta-amyloid
inevitably be pivotal in facilitating the
and
development an effective therapy for AD
lead
to
AD
of
pathology.
both
oligomers/plaques
hyperphosphorylated tau neurofibrillary tangles. Both common features of AD can then over-activate more kinases to further reduce axonal transport, feeding
in the future.
Bibliography. Books.
into the cycle of axonal swelling and a
Cassimeris L., Vishwanath R.L. and Plopper
mass
G. (2010) Lewin’s Cells 2nd Edition. pp. 529-
of
neuronal
death
in
the
hippocampus and basal forebrain.
542. Jones and Bartlett, Massachusetts. Rang H.P., Ritter J.M., Flower R.J., and
An alternative hypothesis for the cause
Henderson G. (2015) Rang and Dale’s
of
Pharmacology 8th Edition. pp. 487-489.
from
evidence
that
hyperphosphorylated tau neurofibrillary tangles
can
function
by
trigger
reduced
inhibiting
kinesin
motor
Elsevier, Philadelphia. Journals.
and
dynein from binding to microtubules
Agholme L., Nath S., Domert J., Marcusson
(Dixit et al., 2008). Tau’s actions on
J., Kagedal K. and Hallbeck M. (2014)
microtubule motors leads to axonal transport defects which may begin AD pathogenesis. This implies that tau, rather than dysfunctional microtubule
Proteasome inhibition induces stress kinase dependent transport deficits—implications for
Alzheimer’s
disease.
Molecular
and
Cellular Neuroscience. 58, 29–39.
motors, may be the key initiator of AD.
Arimoto M., Koushika S.P., Choudhary B.C.,
Equally, some studies have suggested
Li C., Matsumoto K. and Hisamoto N. (2011)
that tau does not have any effect on
The Caenorhabditis elegans JIP3 Protein
motor function or axonal transport
UNC-16 Functions as an Adaptor to Link
(Yuan et al., 2013). Thus, its role in AD pathogenesis
and
effect
on
motor
Kinesin-1 with Cytoplasmic Dynein. Journal of Neuroscience. 31, 2216-2224.
proteins is still subject to debate. To
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
28
comes
Page
AD
Cavalli V., Kujala P., Klumperman J. and
Gao F.J., Hebbar S., Gao X.A., Alexander
Goldstein L.S. (2005) Sunday Driver links
M., Pandey J.P., Walla M.D., Cotham W.E.,
axonal transport to damage signaling. The
King S.J. and Smith D.S. (2015) GSK-3ß
Journal of Cell Biology. 168, 775–787.
Phosphorylation
of
Cytoplasmic
Dynein
Reduces Ndel1 Binding to Intermediate Del Ser T., Steinwachs K.C., Gertz H.J.,
Chains and Alters Dynein Motility. Traffic.
Andrés M.V., Gómez-Carrillo B., Medina M.,
16, 941-961.
Vericat J.A., Redondo P., Fleet D. and León T. (2013) Treatment of Alzheimer’s disease
Gunawardena S., Yang G. and Goldstein
with the GSK-3 inhibitor tideglusib: A pilot
L.S.B (2013) Presenilin controls kinesin-1
study. Journal of Alzheimer’s Disease. 33,
and dynein function during APP-vesicle
205-215.
transport
in
vivo.
Human
Molecular
Genetics. 22, 3828-3843. Dixit R., Ross J.L., Goldman Y.E. and Differential
Jope R.S. and Johnson G.V.W. (2004) The
regulation of dynein and kinesin motor
glamour and gloom of glycogen synthase
proteins by tau. Science. 319, 1086–89.
kinase-3. Trends in Biochemical Sciences.
Holzbaur
E.L.F.
(2008)
29, 95-102. Duncan J.E. and Goldstein L.S. (2006) The genetics of axonal transport and axonal
Khan S.S. and Bloom G.S. (2016) Tau: The
transport disorders. PLoS Genetics. 2, e124.
Center of a Signaling Nexus in Alzheimer’s Disease. Frontiers in Neuroscience. 10,
Encalada S.E. and Goldstein L.S.B. (2014)
Article 31.
Biophysical Challenges to Axonal Transport: Motor-Cargo
Deficiencies
Neurodegeneration.
Annual
Review
and
Koushika S.P., Schaefer A.M., Vincent R.,
of
Willis J.H., Bowerman B. and Nonet M.L. (2004) Mutations in Caenorhabditis elegans
Biophysics. 43, 141-169.
cytoplasmic Eschbach
J.
and
Dupuis
L.
dynein
components
reveal
(2011)
specificity of neuronal retrograde cargo.
Cytoplasmic dynein in neurodegeneration.
Journal of Neuroscience Research. 24, 3907–
Pharmacology and Therapeutics. 130, 348-
3916.
363. Kulić I.M., Brown A.E.X., Kim H., Kural C., Fox L.M., William C.M., Adamowicz D.H.,
Blehm B., Selvin P.R., Nelson P.C. and
Pitstick R., Carlson G.A. and Spires-Jones
Gelfand V.I. (2008) The role of microtubule
T.L.
not
movement
neurofibrillary aggregates, disrupt neural
transport.
system integration in a tau transgenic
Academy of Sciences. 105, 10011–10016.
Journal
of
tau
species,
Neuropathology
in
bidirectional
Proceedings
of
the
organelle National
&
Experimental Neurology. 70, 588–95.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
29
Soluble
Page
model.
(2011)
LaPointe
N.E.,
Morfini
G.,
Pigino
G.,
the Neuronal Cytoskeleton. International
Gaisina I.N., Kozikowski A.P., Binder L.I.
Journal
of
Alzheimer’s
and Brady S.T. (2009) The amino terminus
Article ID:910502.
Disease.
2013,
of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity.
Morel M., Héraud C., Nicaise C., Suain V.,
Journal of Neuroscience Research. 87, 440-
Brion J.P. (2012) Levels of kinesin light
451.
chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s
Lei P., Ayton S., Bush A.I. and Adlard P.A.
disease:
(2011)
transport. Acta Neuropathologica. 123, 71–
GSK-3
Diseases.
in
Neurodegenerative
International
Alzheimer’s
Disease.
Journal
2011,
Article
of
implications
for
axoplasmic
84.
ID Morfini G and Pigino G (2007) Tau binding
189246.
to microtubules does not directly affect Magnani E., Fan J., Gasparini L., Golding
microtubule-based vesicle motility. Journal
M., Williams M., Schiavo G., Goedert M.,
of Neuroscience Research. 85, 2620-2630.
Amos
L.A.,
Spillantini
M.G.
(2007)
Interaction of tau protein with the dynactin
Morihara T., Hayashi N., Yokokoji M.,
complex. EMBO. 26, 4546–4554.
Akatsu H., Silverman M.A., Kimura N., Sato M., Saito Y., Suzuki T., Yanagida K.,
Mandelkow E-M. and Mandelkow E. (2012)
Kodama T.S., Tanaka T., Okochi M., Tagami
Biochemistry
and Cell Biology of Tau
S., Kazui H., Kudo T., Hashimoto R., Itoh
Protein in Neurofibrillary Degeneration.
N., Nishitomi K., Yamaguchi-Kabata Y.,
Cold
Tsunoda T., Takamura H., Katayama T.,
Spring
Harbour
Perspectives
in
Medicine. 2, a006247.
Kimura R., Kamino K., Hashizume Y., and Takeda M. (2014) Transcriptome analysis of
Masters C.L., Bateman R., Blennow K.,
distinct mouse strains reveals kinesin light
Rowe C.C., Sperling R.A. and Cummings
chain-1
J.L. (2015) Alzheimer’s disease. Nature
accumulation modifier. Proceedings of the
Reviews Disease Primers. 1, Article 15056.
National Academy of Sciences. 111, 2638-
as
an
amyloid-ß
2643.
transport deficits and neurodegenerative
Mudher A., Shepherd D., Newman T.A.,
diseases. Nature Reviews Neuroscience. 14,
Mildren P., Jukes J.P., Squire A., Mears A.,
161-176.
Drummond J.A., Berg S., MacKay D., Asuni
D.S. and Petratos S (2013) The BetaAmyloid Protein of Alzheimer’s Disase:
A.A., Bhat R. and Lovestone S. (2004) GSK3β inhibition reverses axonal transport defects
and
behavioural
phenotypes
in
Communication Breakdown by Modifying
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
30
Mokhtar S.H., Bakhuraysah M.M., Cram
Page
Millecamps S. and Julien J.P. (2013) Axonal
splicing
Drosophila. Molecular Psychiatry. 9, 522–
retrograde
axonal
transport
of
530.
neurotrophins. Brain Research Reviews. 33, 169-178.
Müller
U.C.
and
Zheng
H.
(2012)
Physiological Functions of APP Family
Sherman M.A., LaCroix M., Amar F., Larson
Proteins. Cold Spring Harbour Perspectives
M.E., Forster C., Aguzzi A., Bennett D.A.,
in Medicine. 2, a006288.
Ramsden M. and Lesné S.E. (2016) Soluble Conformers of Aß and Tau Alter Selective
Nguyen T.V.V, Galvan V., Huang W.,
Proteins
Banwait S., Tang H., Zhang J. and Bredesen
Journal of Neuroscience. 36, 9647-9658.
D.E.
(2008)
Alzheimer
Signal
disease:
transduction
p21-activated
Governing
Axonal
Transport.
in
kinase
Spires-Jones T.L. and Hyman B.T. (2014)
signaling requires C-terminal cleavage of
The Intersection of Amyloid Beta and Tau at
APP at Asp664. Journal of Neurochemistry.
Synapses in Alzheimer’s Disease. Neuron.
104, 1065–1080.
82, 756-771.
Peineau S., Taghibiglou C., Bradley C.,
Stamer K., Vogel R., Thies E., Mandelkow E.
Wong T.P., Liu L., Lu J., Lo E., Wu D., Saule
and Mandelkow E.M. (2002) Tau blocks
E., Bouschet T., Matthews P., Isaac J.T.R.,
traffic of organelles, neurofilaments, and
Bortolotto Z.A., Wang Y.T. and Collingridge
APP vesicles in neurons and enhances
G.L. (2007) LTP inhibits LTD in the
oxidative stress. Journal of Cell Biology.
hippocampus via regulation of GSK3beta.
156, 1051-1063.
Neuron. 53, 703-717. Szpankowski Pigino G., Morfini G., Atagi Y., Deshpande
Goldstein
A.,
colocalization
Yu
C.,
Jung-Bauer
L.,
LaDu
M.,
L.,
Encalada
L.S.B.
S.E.
(2012)
reveals
Subpixel
amyloid
kinesin-1
and
precursor
Busciglio J. and Brady S. (2009) Disruption
protein-dependent
and
dynein
of fast axonal transport is a pathogenic
association with axonal vesicles. Proceedings
mechanism for intraneuronal amyloid beta.
of the National Academy of Sciences USA.
Proceedings of the National Academy of
109, 8582–8587.
Sciences. 106, 5907-5912. Terwel D., Muyllaert D., Dewachter I., Quraishe S., Cowan C.M., Mudher A. (2013)
Borghgraef P., Croes S., Devijver H. and
NAP
Van Leuven F. (2008) Amyloid Activates
in
a
Drosophila
neuronal model
of
GSK-3ß to Aggravate Neuronal Tauopathy
tauopathy. Molecular Psychiatry. 18, 834–
in
Bigenic
Mice. American
Journal
of
842.
Pathology. 172, 786-798.
Reynolds A., Bartlett S. and Hendry I.
Verhey K.J., Meyer D., Deehan R., Blenis J.,
(2000) Molecular mechanisms regulating the
Schnapp B.J., Rapoport T.A. and Margolis
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
31
dysfunction
rescues
Page
(davunetide)
B. (2001) Cargo of Kinesin Identified as Jip
Weaver C, Leidel C, Szpankowski L, Farley
Scaffolding
Associated
N.M., Shubeita G.T. and Goldstein L.S.
Signaling Molecules. Journal of Cell Biology.
(2013) Endogenous GSK-3/shaggy regulates
152, 959-970.
bidirectional axonal transport of the amyloid
Proteins
and
precursor protein. Traffic. 14, 295–308. Verhey K.J. and Hammond J.W. (2009) Traffic control: regulation of kinesin motors.
Yuan A., Kumar A., Peterhoff C., Duff K.
Nature Reviews Molecular Cell Biology. 10,
and Nixon R.A. (2008) Axonal transport
765-777.
rates in vivo are unaffected by tau deletion or overexpression in mice. Neuroscience. 28,
Vicario-Orri E., Opazo C.M. and Muñoz F.J. (2015)
The
Pathophysiology
of
1682-1687.
Axonal
Transport in Alzheimer’s Disease. Journal of
Yuan A., Kumar A., Sasaki T., Duff K. and
Alzheimer’s Disease. 43, 1097-1113.
Nixon R.A. (2013) Global axonal transport rates are unaltered in htau mice in vivo.
Vossel K.A., Zhang K., Brodbeck J., Daub
Journal of Alzheimer’s Disease. 37, 579–586.
A.C., Sharma P., Finkbeiner S., Cui B., Mucke L. (2010) Tau reduction prevents beta amyloid-induced defects in axonal transport. Science. 330, 10-13. Wang Z-X., Tan L. and Yu J-T. (2015) Axonal Transport Defects in Alzheimer’s Disease. Molecular Neurobiology. 51, 1309-
WHO (World Health Organization) (2016) Dementia
fact
Available
sheet. at:
http://www.who.int/mediacentre/factsheets/f s362/en/ (Accessed on 6th February 2017)
Page
32
1321.
Websites.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Divergent evolution of Crocodylus porosus and Gavialis gangeticus cranial morphology Aramish Fatima Faculty of Biology, Medicine and Health, The University of Manchester, U.K.
Abstract A brief overview of the current literature describing the reasons for the divergence in crocodylian skull morphology based on molecular and anatomical data. Differential diet and habitat due to their respective niche occupation has been suggested as a driver for this divergence. Here I have briefly outlined the major developments in our understanding of natural selection driving evolution of exaggerated traits in crocodylians.
Introduction
Figure 2 A schematic drawing of the skull of G. gangeticus depicting the major cranial bones
teeth which are proportionally smaller compared to their body size (Fig. 2).
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
33
Gavialis gangeticus, or the Indian Gharial, is the only living species of the genus Gavialis. As the name suggests, they are only found in the Indian subcontinent, primarily the river systems of South East India (Brochu, 2003), since they are best adapted for freshwater systems. Their most distinctive feature is their elongated, slender snout with reduced palatal fenestrae and an increased number of
Figure 1 A diagrammatic representation of the skull of C. porosus, identifying the major cranial bones.
Page
Crocodylus porosus, commonly known as the saltwater crocodile, is the largest and most broadly distributed species of the extant crocodylians. They prefer brackish and salty water, inhabiting regions over the Indo-Pacific, from Northern Australia to the Southern coastal areas of India. Saltwater crocodiles have a flattened, “generalised� (Brochu, 2001) crocodylian snout which is dorsoventrally compressed and tapers gradually toward the narial region (Fig. 1).
Crocodylidae and diverge at the genus level. The two species exhibit signs of divergent evolution in their cranial morphology since their ancestral form is the Crocodylomorpha such as Protosuchus, who had small, rounded snouts. Close observation of the crocodylian skull in the fossil record shows a higher rate of evolution compared to the post-cranial body. This may be due to the fact that crocodylians as a clade have one of the slowest rate of genome-wide molecular evolution and base substitutions in the animal kingdom (Green et al., 2014). The crocodylian skull is phylogenetically plastic showing a varying degree of adaptive radiation and morphological fluctuations over time (Brochu, 2001). As shown by Pierce, et al, (2009) there is no strong correlation between phylogeny and skull morphology, suggesting other factors such as environment rather than evolutionary proximity drive changes in crocodylian skull shape (Pierce, Angielczyk and Rayfield, 2009).
I hypothesise that the divergence in the morphology of the crocodylian skulls is due to differential selection pressures exerted by the availability of a variety of prey, adaptations to which allowed the crocodylians to occupy different niches in the same ecosystem. It is also of importance that both the taxa occupy
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
34
Fossil evidence suggests that crocodylians originated in the late Permian/early Triassic, 250 MYA (Janke et al., 2005). The order Crocodylia consists of two major families, the Crocodylidae and the Alligatoridae (Fig. 3). Crocodylidae and Gavialidae are two closely related extant taxa, collectively known as the Longirostres (longsnouted), which split off from the Alligatoridae approximately 103 MYA (St John et al., 2012) in the late Cretaceous (Fig. 3), while the split between the Gavialis and Crocodylus genus happened around 80 MYA (Janke et al., 2005). C. porosus and G. gangeticus belong to the family
Page
Figure 3: Close phylogenetic relationships of C. porosus and G. gangeticus illustrating a split from Allgatoridae in the last Cretaceous along with number of species and distribution.
In case of the Indian gharial, the ‘verticalisation’ of the snout during growth is recorded, showing the proportionally longest snout in the extant taxa (Pierce et al., 2008). According to Gold, et al., 2014 ‘the basisphenoid and basioccipital ventrally expand, changing the shape and orientation of the median Eustachian canal’. Since all crocodylians are diapsids, the skull has two pairs of holes, one pair located on the dorsal surface of the skull, the other ventrally (Fig. 1, 2).
Brochu, C. (2001). Crocodylian Snouts in Space and Time: Phylogenetic Approaches Toward Adaptive Radiation. American Zoologist, 41(3), pp.564-585. Brochu, C. (2003). PHYLOGENETIC APPROACHES TOWARD CROCODYLIAN HISTORY. Annual Review of Earth and Planetary Sciences, 31(1), pp.357-397. Cuff, A. and Rayfield, E. (2013). Feeding Mechanics in Spinosaurid Theropods and Extant Crocodilians. PLoS ONE, 8(5), p.e65295. DENSMORE, L. and OWEN, R. (1989). Molecular Systematics of the Order Crocodilia. American Zoologist, 29(3), pp.831-841. Gold, M., Brochu, C. and Norell, M. (2014). An Expanded Combined Evidence Approach to the Gavialis Problem Using Geometric
Green, R., Braun, E., Armstrong, J., Earl, D., Nguyen, N., Hickey, G., Vandewege, M., St. John, J., Capella-Gutierrez, S., Castoe, T., Kern, C., Fujita, M., Opazo, J., Jurka, J., Kojima, K., Caballero, J., Hubley, R., Smit, A., Platt, R., Lavoie, C., Ramakodi, M., Finger, J., Suh, A., Isberg, S., Miles, L., Chong, A., Jaratlerdsiri, W., Gongora, J., Moran, C., Iriarte, A., McCormack, J., Burgess, S. , Edwards, S., Lyons, E., Williams, C., Breen, M., Howard, J., Gresham, C., Peterson, D., Schmitz, J., Pollock, D., Haussler, D., Triplett, E., Zhang, G ., Irie, N., Jarvis, E., Brochu, C., Schmidt, C., McCarthy, F., Faircloth, B., Hoffmann, F., Glenn, T., Gabaldon, T., Paten, B. and Ray, D. (2014). Three crocodilian genomes reveal ancestral patterns of evolution among archosaurs. Science, 346(6215), pp.1254449-1254449. Janke, A., Gullberg, A., Hughes, S., Aggarwal, R. and Arnason, U. (2005). Mitogenomic Analyses Place the Gharial (Gavialis gangeticus) on the Crocodile Tree and Provide Pre-K/T Divergence Times for Most Crocodilians. Journal of Molecular Evolution, 61(5), pp.620-626. Pierce, S., Angielczyk, K. and Rayfield, E. (2009). Shape and mechanics in thalattosuchian (Crocodylomorpha) skulls: implications for feeding behaviour and niche partitioning. Journal of Anatomy, 215(5), pp.555-576. St John, J., Braun, E., Isberg, S., Miles, L., Chong, A., Gongora, J., Dalzell, P., Moran, C., Bed'Hom, B., Abzhanov, A., Bur gess, S., Cooksey, A., Castoe, T., Crawford, N., Densmore, L., Drew, J., Edwards, S., Faircloth, B., Fujita, M., Greenwold, M., Hoffmann, F., Howard, J., Iguchi, T., Janes, D., Khan, S., Kohno, S., de Koning, A., Lance, S., McCarthy, F. and McCormack, J. (2012). Sequ encing three crocodilian genomes to illuminate the evolution of archosaurs and amniotes. Genome Biology, 13(1), p.415. Timetree.org. (n.d.). TimeTree :: The Timescale of Life. [online] Available at: http://www.timetree.org [Accessed 19 Nov. 2017].
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
35
References
Morphometric Data from Crocodylian Braincases and Eustachian Systems. PLoS ONE, 9(9), pe105793.
Page
different habitat - brackish and freshwater respectively. Gharials are primarily piscivorous while most crocodiles are dietary generalists as adults, eating any animal matter they can swallow. As the two species were sympatric in the past (Rao, Choudhury, 1990), this radiative adaption would have allowed them to fill different niches in the same ecosystem. Large, flattened skull morphologies like the crocodiles tend to utilise ambush methods to capture food, since they have a stronger jaw to hold and drown larger terrestrial prey, with ‘death roll’ inertial feeding being used to break down prey whilst the narrower rostrum of Gavialis often use slashing behaviours to capture fish (Cuff and Rayfield, 2013). Due to this adaptation, Gharials have the highest fishing success compared to other crocodylians (Thorbjarnarson, 1990). Consequently, extreme snout elongation can be suggested to be oriented towards increasing the efficiency of capturing small, mobile prey (Pierce, Angielczyk and Rayfield, 2009).
The Importance of Cloud Forest Ecosystems and the Challenges They Face Flora Matilda Jefferson Tickell Faculty of Biology, Medicine and Health, The University of Manchester, U.K.
expansion of both agriculture and urban
Abstract
projects leading to deforestation. It is vital Cloud forests are some of the most unique
that the full importance and fragility of
and important ecosystems on the globe.
cloud
Extremely dependent on cloud cover and
towards
the presence of epiphytes, cloud forests
extraordinary ecosystems.
contain
unusually
high
numbers
forests
is
the
understood
preservation
to of
work these
of
endemic species and show some of the highest
levels
of
biodiversity
of
all
Introduction
terrestrial habitats due to their unique biology and formation. Constant humidity
From the base to the summit of a
is the most important prerequisite for the
mountain in the tropics, there are several
development of cloud forests and their
distinct
unique
structure.
Cavelier and Goldstein in 1989, the first is
Constant water input results in the
Lowland Rainforest, found at the lowest
persistent washing-away of moisture and
altitude.
nutrients which leads to stunted tree
Rainforest forms. These two environments
growth. Furthermore, due to their reliance
rely on rainfall as their primary supply of
on high levels of humidity from the
water and are traditionally recognised as
perpetual
fog,
extremely
vulnerable
cloud to
Above
As
defined
by
this, Lower Montane
forests
are
supporting high levels of biodiversity
changes
in
(Myers et al., 2000). At higher altitudes is
climate and weather patterns, and loss of
found
cloud at suitable altitudes will ultimately
Montane
lead to the loss of cloud forest systems.
Goldstein,
With this loss comes the extinction of
Rainforest can also be defined as a
many species of plants and animals.
Tropical Montane Cloud Forest, or, more
Humans further exacerbate the effects of
simply, ‘cloud forest’ and represents one of
the loss of cloud cover as cloud forests are
the
increasingly
ecosystems
encroached
upon
by
the
the
most
unique
ecology
Rainforest 1989).
(Cavelier Upper
interesting on
of
the
Upper and
Montane
and
fragile
globe.
Found
predominantly in South America and Asia,
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
36
the
and
types.
Page
development
forest
and to a lesser extent in Africa (Toledo-
play a role in cloud forest classification,
Aceves et al., 2011), cloud forests are
allowing tropical forests as low as 1000m
thought to make up 14% of tropical forests
above sea level to be defined as cloud
worldwide, though some estimates put
forests due to ecological conditions and
that figure as low as 2.5% (Toledo-Aceves
species composition (Stadtm端ller, 1987).
et al., 2011). Either way, they are
Other characteristics of cloud forests
uncommon yet extremely important.
include
the
extremely
fact
high
that
levels
they of
support
biodiversity
despite having soils with low levels of Forests that are classified as cloud forests
nutrients,
exhibit several key characteristics. Firstly,
unusually high levels of endemic species
they are in near-perpetual low-level cloud
(Soethe et al., 2008; Toledo-Aceves et al.,
cover. This means that the air is highly
2011; Wilson and Rhemtulla, 2016).
humid and the water input comes mainly from horizontal precipitation (fog) as opposed to vertical precipitation (rain)
and
that
they
support
The presence of epiphytes is also a key feature of cloud forests (Holder, 2004);
Figure 1. Diagram to show the movement of water vapour from the ocean to mountainous areas and its precipitation at certain altitudes. Between altitudes of ~1,500 and ~3,300m, cloud forms, and in the mountains, this becomes a fog, providing the conditions needed for cloud forest ecosystems to thrive. (Adapted from Figure 1 of Scholl M et al., 2011)
(Stadtm端ller, 1987). This immediate cloud
these plants exhibit both the ability to
cover is only achieved in forests above a
thrive at high altitudes due to the high
certain altitude; mainly in the zone
humidity
between 1,500 and 3,300 meters above sea
believed to actually contribute to the
level (Stadtm端ller, 1987; Leo, 1995). This
maintenance
being said, different environmental factors
(Stadtm端ller, 1987). On the unstable and
of
high
they
are
humidity
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
37
importantly,
Page
and,
often steep slopes of montane cloud forests
formed (Li et al., 2016). When this occurs
many hundreds of tree species grow, yet
over the Pacific, a sea fog forms which
they exhibit stunted growth and are
moves inland to feed the cloud forests of
unable to reach the towering heights of
Central
tropical forests found at lower altitudes
(Beiderwieden et al., 2005). ‘Steam fog’ is
(Cavelier and Goldstein, 1989). Some
generated in a slightly different way; it is
cloud forests exhibit such stunted growth
formed when the water is warmer than
that they are termed ‘elfin forests’, with
the air above it. This cool air is unable to
trees sometimes reaching a maximum of
take up more moisture, so excess water
only eight meters (Cavelier and Goldstein,
vapour condenses into water droplets,
1989; Cordero, 1999; Holder, 2004).
forming clouds (Heo et al., 2010; Scholl et
and
Southern
America
al., 2011). Both sea fog and steam fog are forms of advection fog as they are formed
Key
Features
of
Cloud
over bodies of water and then are moved
Forests
by the wind into the mountains where
The Clouds of the Cloud Forest – how
Scholl et al., 2011). Cloud forests can also
and why do they occur?
be supplied by ‘radiation fog’, which unlike
they settle (Beiderwieden et al., 2005;
As stated above, one of the key features of a cloud forest is regular, if not persistent,
the other aspects of the hydrological cycle does not form
cloud immersion (Foster, 2001). This cloud
over water bodies. Radiation fog forms
cover
a
overnight in valleys when temperatures
perpetual ‘fog’, which is defined as cloud
cool, as valleys in tropical zones are
that touches the ground and has a
extremely humid and hold a great deal of
visibility of less than one kilometre (Scholl
water themselves (Scholl et al., 2011).
could
also
be
described
as
et al., 2011; Li et al., 2016). As with all
supplied
by
oceanic
water
vapour.
The significance of constant humidity Unlike
most
other
rich
and
dense
However, there are other ways in which
ecosystems around the world, cloud forests
this can be generated. ‘Sea fog’ is created
do not rely on rain as their primary water
when warm air moves over ocean waters
source. Although winds may disturb the
which are cooler than the air above them.
clouds causing frequent rain showers, the
As a result, water evaporates, rising and
cloud
cooling to form water vapour. The water
precipitation of the fog alone is enough to
vapour then condenses and clouds are
feed
cover the
is
plants
so
heavy
(Holder,
that 2004).
the For
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
38
by the hydrological cycle, and is mainly
Page
clouds, the fog of cloud forests is generated
example, in Columbian rainforest 48% of
lower than the maximum height of trees in
the water input into the ecosystem comes
lowland
from
and
Nineteen meters represents a tall tree in
Goldstein, 1989). This is significant as
cloud forests (Soethe et al., 2008), whereas
water from rainfall is primarily stored in
rainforest trees are known to exceed 45
the canopy of the forest, whereas fog
meters (Small et al., 2004). One reason
precipitation supplies both the understory
that this occurs is due to the heavy
and overstory with water, and therefore
moisture load of the air limiting plant
represents a more efficient supply to all of
transpiration
the plant species in the area (Holder,
Transpiration
2004). Though in the fog itself there is a
transport of the nutrients and water taken
high quantity of water, the moisture of the
up by the roots up the body of the plant,
fog and cloud must be captured by the
and is also involved in the cooling of the
plants, and both the canopy of the forest
leaves necessary for high photosynthetic
and the abundance of epiphytes are
efficiency (von Caemmerer and Baker,
extremely
making
2007). Water evaporates through the open
precipitation available for plants (Holder,
stomata when CO2 exchange occurs, and
2004). Different areas of the forest will
this evaporation effectively draws water
have different levels of water supply due
up through the plant due to water tension
to the way the canopy interacts with the
(von Caemmerer and Baker, 2007). In the
fog allowing precipitation to enter the
Cloud Forests, water molecules collect on
ecosystems. This can be affected by the
leaves and block the normal process of
height and structure of the canopy, leaf
transpiration as water vapour cannot be
surface
forest
released from the leaf stomata. This is
orientation and latitude (Cavelier and
associated with a reduction in plant
Goldstein, 1989; Holder, 2004). The fog
primary productivity (StadtmĂźller, 1987).
itself can be impacted on by the species
Transpiration
composition in different areas of the forest,
physically blocked by the high quantities
as different species have different canopy
of lichens and bryophytes which are
structure and leaf shape (Holder, 2004).
favoured by the humid environment of
and
important
margin,
(Cavelier
in
and
the
Although constant cloud cover is a vital aspect of the cloud forest, it is associated with the reduced productivity of cloud forest ecosystems. This is observed in the height of the trees; as previously stated their average maximum height is much
1999).
(StadtmĂźller, is
necessary
can
1987). for
additionally
the
be
cloud forests. These collect both on leaves and branches, and this added weight can physically damage the host plant, for example
by
(StadtmĂźller,
breaking 1987).
branches
Therefore,
the
primary productivity of the host tree is reduced as it invests more on damage
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
39
precipitation
(Cordero,
Page
fog
rainforest
repair. Furthermore, the high humidity
tree height is 19m, whereas at 2400m the
provided by cloud cover means water is
maximum tree height is only 12m (Soethe
always entering the system. This results
et al., 2008). The measured primary
in the consistent movement of water
production is also observed to decrease
though the soil and subsequently the
with altitude (Soethe et al., 2008). The
constant washing away of nutrients as
decrease in tree height at higher altitudes
water drains down the mountainside.
may not depend entirely on higher soil
Therefore, the soil has low nutrient levels,
saturation; it has also been hypothesised
in particular low nitrogen levels, and
that the cooler temperatures of the higher
contributes
productivity
altitudes and the denser cloud cover may
limiting the growth of plants and trees in
block some of the sun’s rays leading to low
the cloud forest (Cordero, 1999).
levels of photosynthesis (Cordero, 1999).
In addition to the drainage of water, the
A study by Soethe et al. in 2008 considered
nutrient load of the soil is affected by
how
several other aspects of the environment.
availability. It was hypothesised that at
The quality of the litter entering the
high altitude, despite low nutrients, there
system plays a role; poor quality litter
must be at least a critical level of
entering
low
nutrients that allows some plant growth.
nutrient load. It is thought that limited
It was further hypothesised that lower
root room and anaerobic soils also play a
nutrient levels at higher altitudes may be
heavy role in nutrient limitation (Cordero,
due to low mineralisation rates and
1999).
shallow root systems. Three sites in
the
to
the
low
system offers
only
altitude
can
affect
nutrient
Southern Ecuador were studied, with was found that leaf litter production is
drainage of nutrients plays a role in the
greater at lower altitudes, as the depth of
stunting
therefore
humus was higher, suggesting that more
unsurprising that as the altitude increases
nutrients are recycled back into the
the average size of the trees decreases
system at lower altitudes. This could help
further (Soethe et al., 2008). This is
explain the increased size of trees at lower
because the higher the altitude, the more
altitudes. Higher altitudes were observed
the water and therefore the more the
as having higher rainfall input, suggesting
nutrients drain away. For example, in
that there would be higher levels of water
Ecuadorian rainforest it can be observed
drainage in these areas. Samples of leaves
that at an altitude of 1900m the maximum
and soil taken at the different altitudes
of
trees.
It
is
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Page
It has been shown that in cloud forests the
40
samples taken from different altitudes. It
and
Soethe
nutrient
and
colleagues
levels.
The
measures
samples
their counterparts at lower altitudes. This
were
could be because trees at higher altitudes
analysed for carbon, nitrogen and sulphur
respond to low nutrient levels by reducing
concentrations, as well as other elements
their growth rather than reducing the
important for plant growth; phosphorous,
amount of nutrients they need for high
potassium, calcium and magnesium. In
growth. Subsequently, the nutrients are
the leaves, Soethe and colleagues observed
not found ‘diluted’ in trees at higher
that apart from calcium and magnesium
altitudes, rather they simply grow less to
levels, all other nutrients were found at
maintain nutrient concentrations. It was
significantly higher levels in trees at lower
additionally observed that the artificial
altitudes, with the average difference
addition of nutrients to montane cloud
being between 30% and 48%. In terms of
forests can cause an increase in the
limitation to growth, at the lower altitudes
natural trunk diameter, demonstrating
all nutrient levels were sufficient for tree
that the lack of nutrients is a factor that
growth, however carbon to nitrogen and
stunts growth, and that the trees are not
carbon to phosphorous ratios were lower
genetically small (Soethe et al., 2008).
than those to be expected for temperate plants.
This
has
an
implication
in
Epiphytes and their significance
decomposition rates in the soil (Enriquez
Epiphytes are plants that include most
et al., 1993). These were slower than
orchids, ferns, mosses and bromeliads.
average at higher altitudes and this limited nutrient flow. Furthermore, no limitation to growth due to nitrogen or phosphorous was measured at the lowest altitude. However, though all sites had sufficient nutrient levels, the trees in these cloud forests were still stunted compared to trees in other mountain forests. This suggests that the limitation of light and low temperatures was more important than nutrient limitation in the low level of growth at this altitude. Conversely,
at
higher
altitudes
the
whereas the nutrient levels in the trees were at similar concentrations to those of
Figure 3. Photo to show the fog and heavy epiphyte cover of trees in the Ecuadorian cloud forest in the Bella Vista Reserve, 2017. (picture from author).
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Page
range that is defined as being ‘deficient’,
41
nitrogen levels in the soil were in the
Although they live on the surface of other
onto the epiphytes or down to the forest
species they are not parasites as they take
floor, allowing more water to become
their
the
available to the ecosystem (Holder, 2004).
environment rather than the host plant
In terms of the nutrient cycle, up to half of
(Butler, 2012). There are over 83 families
the NH4+ and NO3- input into the cloud
in the epiphyte group, and they are found
forest ecosystems is transported into the
at their highest abundance in cloud
system via water that is made available
forests, though epiphytes can also be
from epiphytes; this is demonstrated by
found in temperate zones, most notably in
the fact that half of the nutrients in the
the form of moss (Butler, 2012). In cloud
canopy are found not in the trees but in
forests, epiphytes are heavily embedded in
the epiphytes themselves (Foster, 2001).
or on host plants, and the richer the host
Some epiphytes such as mosses are
plant community, the richer the epiphyte
important on the under-canopy of trees as
community, due to the availability of more
they can grow extremely densely and
micro-niches (Foster, 2001; Cach-Perez et
cause a reduction in the productivity of
al., 2013). In Ecuador, epiphytes make up
trees
25% of all vascular plants found in the
(Stadtmüller,
country, and these epiphytes make up 35%
epiphytes are able to change the structure
of the country’s endemic species, and are
of the cloud forest; many epiphytes are
predominantly found in the cloud forests
designed to collect water and therefore can
(Koester et al., 2013). Epiphytes play an
become heavy upon branches of trees.
important role in cloud forest ecosystems.
This
Firstly, and as stated previously, these
therefore disturbance and the formation of
plants
in
secondary forest (Koster et al., 2011). For
maintaining the humidity of the air as
example, bromeliads are often covered in
they can unlock moisture from the fog by
scale-like structures which are able to
inducing
through
absorb water from the air, and the
condensation of fog to water droplets on
structure of the plant is cup-like, allowing
the
The
water to sit within the plant (Armbruster
epiphytes help maintain humidity of the
et al., 2002). This cup structure also
cloud forests even if at the macroclimatic
means that leaf litter collects in the plant,
level
contributing
leaves
the
an
nutrients
important
precipitation (Stadtmüller,
humidity
from
role
1987).
has
dropped
by
leads
blocking
transpiration
1987).
Furthermore,
to
to
branch
breakage
endogenous
and
primary
(Stadtmüller, 1987). This is achieved
production (Richardson et al., 2015). The
because the epiphytes increase the surface
water collected in epiphytes make them an
area of the canopy, thereby increasing the
important habitat for many different
interception of fog droplets and increasing
species including invertebrates, frogs and
the rate that water precipitates, either
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
42
play
and
Page
water
birds by proving both a food and water
(Koester et al., 2013). Species adapted
source (Richardson et al., 2000).
extremely
specifically
to
their
niche,
meaning that they are now unable to disperse
Endemic species of the Cloud Forest
number of endemic species, resulting in high biological uniqueness in these areas (Toledo-Aceves et al., 2011; Koester et al., 2013). Indeed, some epiphytes are not just endemic to a particular cloud forest, but to particular
mountain cloud
peaks forest,
within
and
of
their specific
range.
Furthermore, gene feedback from the
Cloud forests have an unusually high
certain
out
a
endemic
species have even been found in cloud forests less than 10km2 in size (Foster, 2001). This is a result of the geological
centre
of
the
population
prevents
individuals on the outskirts of the range from being able to select for properties that would be advantageous in adjacent ranges. This range restriction results in species
being
more
vulnerable
to
extinction (Koester et al., 2013), meaning that the endemic species of the cloud forests
are
important
in
terms
of
conservation, as many could be lost before they are even identified.
structure of mountains; there is an island
isolated from each other due to decreases in altitude and the formation of valleys, limiting species’ ranges (Foster, 2001). This isolation effect was important in the formation of so many unique endemic species. Species became isolated as the mountains were pushed higher, leading to allopatric speciation (the formation of new species after different populations of the same species become isolated from each other) as populations became further separated and then experienced different selection pressures (Koester et al., 2013). Furthermore, differences in climate at different
altitudes
formed
different
populations which became isolated from each other, again leading to speciation
The loss of endemic species of the cloud forests could result in the loss of many medically useful compounds before they are
discovered.
pharmaceutical
Studies
properties
into of
the
different
plant species in the cloud forest reserve Monteverde in Costa Rica showed that 62% of the plant extracts made had high bioactivity (Setzer et al., 2003). These properties included bactericidal, fungicidal and cytotoxic activities. There is even evidence that suggests some of the plant extracts that have been identified could be used in an anti-cancer context (Setzer, 2011). More research and further testing needs to be carried out to fully appreciate the drug potential of the cloud forest. However
cloud
forests
face
many
challenges and throughout the globe are
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
43
different parts of cloud forest can be
Page
effect in that, though geographically close,
declining in size and abundance at an
Evans, 2010). For example in 2010 there
alarming rate.
was an extremely fast change from El Niño conditions to La Niña conditions, resulting in a huge increase in the sea
challenges
do
cloud
temperature of the Atlantic (Trenberth,
forests face and how can they
2012). The rising temperature of the seas
be prevented?
causes high levels of evaporation. This forms large quantities of water vapour which release heat and therefore increase the
rate
of
global
warming.
More
As with habitats found all over the globe,
pressingly, the changes in El Niño events
climate change presents a huge challenge
in the Pacific have caused sea surface
to cloud forests. Climate change includes
temperatures to increase, resulting in a
changes in temperature, precipitation and
decline in the production of the sea fog
cloud cover. This can lead to hurricanes
that supplies the Andes (Pounds et al.,
and storms, yet also to long dry periods
1999). Along with increases in CO2 levels
(Trenberth, 2012). These changes can be
(Foster, 2001), changes in El Niño events
extremely damaging to most ecosystems,
may also result in the altitude at which
but in particular to the fine balance of
clouds
temperature
that
predicted that within a century the lowest
support cloud forests. This makes cloud
altitude of cloud formation might rise by
forests
threatened
600 meters (Bush, 2002). Therefore, huge
ecosystems (Toledo-Aceves et al., 2011),
swathes of cloud forest will no longer be
and they are often used as ‘early warning
immersed in continual fog (Anchukaitis
systems’ as they are so fragile and can
and Evans, 2010). Due to this effect there
signal any impending widespread effects
are already cloud forests in Costa Rica
of the changing climate (Gasner et al.,
that show signs of declining cloud levels at
2010). Climatic changes that could affect
the altitude of cloud forests (Foster, 2001),
cloud forests include changes in the El
with cloud formation occurring at higher
Niño-Southern
has
altitudes. Furthermore, it is predicted that
short-term
in the Andes and throughout the Amazon
increases in temperature in certain areas,
average temperatures could increase by 3
with the knock-on effect of decreasing
Celsius, and rainfall will decrease by 20%
cloud cover at certain altitudes. However,
(Bush,
any dramatic or long-term changes might
devastating effect on cloud forest species
damage the integral stability of the cloud
that have a huge water-reliance. In terms
forests
of CO2, it is unknown whether or not
always
one
and of
the
precipitation most
Oscillation,
periodically
completely
caused
which
(Anchukaitis
and
form
2002).
becoming
This
higher;
would
it
have
is
a
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
44
Climate Change and Global Warming
Page
What
changes in climate will result in massive
temperatures might favour certain species
uptake of carbon into the forests, thereby
and hinder others, disrupting balances
reducing the effect of CO2 on the climate,
between
or conversely result in the release of
competition
carbon from the forest, exacerbating global
Furthermore, even if species were able to
warming (Fearnside, 2004).
move with the rising altitude of the cloud
predators
and
prey
(Parmesan,
and 2006).
cover, there would be no pristine forest for them to colonise, and therefore high levels
Consequences of declining cloud cover on
of competition may also play a factor in
Cloud Forests
the loss of many cloud forest species
Cloud cover is the fundamental and indispensable condition of montane cloud forest persistence. These habitats are mountainous, and different areas of cloud forest can be likened to islands as
(Foster, 2001). Some of the most sensitive species are epiphytes, which are sensitive to changes in humidity, as well as reptiles, birds and particularly amphibians (Foster, 2001; Parmesan, 2006).
sufficient cloud cover is only possible
range-restricted by the presence of or lack of cloud cover. Range restricted species are known to be at high risk because they are very vulnerable to ecological changes. Therefore, if changes in climate affect the conditions
of
restricted
by
a
species range
range,
due
to
those high
specialisation are often the first to become extinct as they are unable to adapt to new conditions
or
move
to
new
ranges
(Parmesan, 2006). This climate change induced extinction is not only the result of ecological changes within the species range, but could also be due to changes within
community structures, loss
of
habitat and loss of forest cover (Foster, 2001). For example, interactions between species might be affected as warming
Cloud forests are highly dependent on epiphytes.
Epiphytes
are
extremely
vulnerable to climatic change due to their biology: they have no permanent water source and rely on the moisture from the air; they are perennial; and they have coevolved to be extremely specialised to particular
humidities,
altitudes
and
temperatures (Cach-Perez et al., 2013). All of these factors make them vulnerable to any changes in climatic conditions. If epiphytes are lost, cloud forests will not only lose around a quarter of their plants (Foster, 2001), they will also lose a keystone provider of habitat and water to the ecosystems, and there may be loss of many species reliant on the conditions provided by the epiphytes (Foster, 2001). Furthermore,
secondary
forest,
for
example areas damaged by storms or
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
45
species in the cloud forest are extremely
Page
above a certain altitude. Therefore, many
human activity, is less likely to be
montane forests in Costa Rica there was
recolonised to the same level of epiphyte
such
species richness as primary forest as tree
population numbers that it was presumed
composition of secondary forest is less
that it was due to the introduction of a
diverse. Similarly, epiphytes cannot be
pathogen
easily reintroduced into conserved or man-
Batrachochytrium
made habitats due to the same limited
fungus of unknown origin that that thrives
tree species composition. This effect is in
in warm temperatures, and was first
fact seen with most cloud forest species as
recorded in Mexico in the 1970s (Murrieta-
they all occupy such specialised and small
Galindo et al., 2014). It is also the
niches (Foster, 2001).
pathogen that causes the death of many
a
dramatic
reduction
(Pounds
et
in
al.,
frog
1999).
dendrobatidis
is
a
species of harlequin frog, and is partly responsible
for
declining
amphibian
It is observed increasingly frequently that
numbers (Anchukaitis and Evans, 2010).
amphibian species are some of the most
Due to the fungus’s preference for warm
fragile organisms; they are often the first
temperatures,
to be disrupted or to go extinct due to
undeniably the key factor in the loss of
climate change (Parmesan, 2006). Their
these animals, as the changes in air and
complex life cycles and permeable skin
water temperature have directly increased
make
to
the prevalence of this infectious disease
changes in their environment (Lips, 1998).
and many others. The effect of pathogens
The amphibians of the tropics thrive in
on amphibians is exacerbated as climate
cloud forests due to the high and constant
change shifts the range of cloud cover,
humidity (Foster, 2001). However, cloud
moving it to a higher altitude and
forests are fragile ecosystems, meaning
therefore producing longer periods of dry
that amphibians in these regions are
at lower altitudes; this essentially shrinks
probably at more risk than their lowland
the areas of functional cloud forest,
counterparts. A stark example to illustrate
pushing remaining species and individuals
the case is the decline of the harlequin
closer together and increasing the spread
frogs of Southern and Central America. In
of diseases both fungal and bacterial
both rainforests and cloud forests a
(Pounds et al., 1999).
them
extremely
vulnerable
climate
change
is
staggering 67% reduction in numbers was Amphibians are not the only animals that
frequencies do fluctuate directly with
are expected to be hugely effected by
natural changes in weather, through the
changes in climate. Research by Gasner et
1980s, and in 1987 in particular, in
al., 2010, predicted that half of bird
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Page
2000s (Parmesan, 2006). Although anuran
46
observed from the mid 1980s to the mid
species found in montane ecosystems are
suggest
expected to decline in the coming years,
intermediate levels of human disturbance
and that seven out of eight species
(as opposed to high or low levels) have the
endemic to the cloud forest ecosystems in
highest proportion of endemic species.
Costa Rica and Panama are expected to
This may be because the low levels of
become
in
disturbance prevent competitive species
temperature and rainfall (Gasner et al.,
from invading the niches of the endemic
2010) and increasing use of pesticides
species (Kessler, 2001). High levels of
(Hallmann et al., 2014). Although larger
human disturbance favour the formation
cloud
of secondary forest, that is forest that has
extinct
forest
mountain
due
mammals
gorillas
of
to
changes
such the
as
the
Democratic
been
that
areas
disturbed
that
either
High
levels
experience
naturally of
or
Republic of Congo or the spectacled bear of
unnaturally.
human
the Andes will probably not be directly
disturbance include clear-cutting or slash
affected by changes in weather patterns
and burn, resulting in areas which can
due to climate change, the loss the
only be colonised by one or two hardy
suitable habitat and food sources will lead
pioneer species. This means that areas
to a collapse in their numbers (Foster,
where there have been high levels of
2001).
human disturbance become dominated by certain species, and are unable to return to their original levels of biodiversity
change and its effect on the cloud forests is down to human activity, humans also hugely affect the cloud forests in more direct
ways,
in
particular
through
these pioneer trees are often smaller and therefore have the potential to support few, if any, epiphytes. Epiphyte diversity is always found at its highest in primary, undisturbed forest (Koster et al., 2011).
deforestation or agriculture (though these
Deforestation of cloud forests is carried
often come hand in hand). It has been
out to clear land for either agriculture or
observed that the higher the human
expanding urban areas and, due to this,
population density, the more problems
60% of tree species in cloud forests are
there are for the cloud forest and the more
threatened by extinction (Toledo-Aceves et
the cloud forests are at risk of extinction
al., 2011; Toledo-Aceves et al., 2014). 1.1%
(Toledo-Aceves et al., 2011). This being
of all cloud forests are lost each year due
said, studies into the effect of human
to commercial logging, and in some areas,
disturbance on levels of species and
for example in South-East Asia where
community interactions in the cloud forest
there are 32 million hectares of cloud
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
47
Though it is undisputable that the climate
(Koster et al., 2011). In addition to this,
Page
Human Interactions with Cloud Forest
forest, these ecosystems are being lost 23%
up to higher altitudes, where they then
more rapidly than rainforests in the same
condense on the plants of the cloud forest
latitude (Peh et al., 2011). In the case of
in a similar way to fog and cloud (Daly et
agriculture, the clearing of trees is often
al., 2007; Sodhi, 2012). As bromeliads play
carried out on the small scale, with
in huge role in the condensation of fog into
individual land owners encroaching a little
the ecosystems, it is unsurprising that it
on the forest each year by clearing it for
has been found that the water within
firewood or smallholdings crops (Toledo-
bromeliads
Aceves et al., 2011). However, in Mexico,
concentration of pesticides of all standing
50% of deforestation of the cloud forest has
waters (Shunthirasingham et al., 2011).
occurred to free up land for large-scale
As
cattle industry or industrial crops (Toledo-
numerous different species including both
Aceves et al., 2011). In particular, coffee
terrestrial
grows extremely well in the soil of low-
many
lying cloud forests. As coffee production
concentrations of pesticides (Richardson et
has
years,
al., 2015). However, pesticides do not only
further
affect their target - the insects – they can
upland into undisturbed cloud forests
also have a debilitating effect on full
(Holder, 2004) and the shade these crops
ecosystems. For example, in areas where
need is provided predominantly by non-
high concentrations of neonicotinoid are
native trees which further disturbs cloud
found, bird populations have declined by
forest systems (Murrieta-Galindo et al.,
an average of 3.5% a year (Hallmann et
2014).
al., 2014). This could be due to the direct
boomed
plantations
over
the
have
recent
encroached
contains
discussed,
of
ingestion
and
bromeliads aquatic
which
of
the
the
are
highest
harbour
invertebrates,
killed
pesticides
by
in
high
high
concentrations or through the loss of their In addition to the clearance of cloud forest
primary food source. Alongside changes in
for land, agricultural practices can also be
climatic conditions, high concentrations of
detrimental to cloud forest vitality. It has
chemicals such as pesticides are also
been
Rica,
thought to wreak havoc on amphibian
and
populations, due to their permeable skin
such
as
in
Costa
endosulphan
chlorothalonil used on the low lying
that
agricultural plantations in valleys or
chemicals into their system (Lips, 1998).
upwind of national parks are affecting
allows
for
easy
absorption
of
cloud forests on the slopes of the nearby
How can Cloud Forests be
mountains
protected and restored?
(Daly
et
al.,
2007).
The
pesticides vaporise in the valleys, allowing winds and rising warm air to move them
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
48
pesticides
that
Page
observed
Although the list of threats to cloud forest
reserves not only protect the cloud forest
ecosystems is a long one, there are many
for future generations, but also boost the
projects and organisations whose primary
tourism
aim is to protect the integrity of these
ecologists, conservationists, students and
fragile habitats. On the small scale, there
people who want to experience something
are simple changes to farming practises
new are more likely to visit areas of cloud
that can be applied on plantations, for
forest that are protected from encroaching
example using cloud forest trees as shade
industry. However, on an even larger
trees when dividing up land, rather than
scale, the only way to really save the cloud
non-native trees. This reduces the volume
forests would be to slow down, or more
of forest that is destroyed when creating
ideally, completely prevent climate change
areas of agriculture and provides corridors
induced by human actions. This is the only
for wildlife to move through, preventing
conceivable way to fully protect the cloud
areas of the cloud forest from being
forests as the problem is so large that
isolated
2011).
there is at this stage no way to control it;
Similarly, it has been heavily advised that
we cannot physically make clouds form at
in the planning of new urban or suburban
the same altitude they did 10 years ago,
areas, similar corridors should be left to
however we can try to prevent the
remain
situation from getting any worse.
(Toledo-Aceves
therefore
et
al.,
preventing
the
industry
as
bird
watchers,
fragmentation of cloud forests (Toledoal.,
2011).
Other
recommendations to urban planners from conservationists
include
host
plant
conservation to save the epiphytes, which are not easily reintroduced into new plantations (Cach-Perez et al., 2013). On a larger scale, governments are increasingly putting aside large areas of cloud forest as protected areas of reservation, or limiting the
amount
of
deforestation
Conclusion
legally
allowed in certain areas. For example, in 2015 the Columbian government declared 150,000 acres of unspoilt cloud forest as areas of reservation, and by doing so protected over 300 bird species that are under threat of extinction (Gaworecki, 2015). Countries that form cloud forest
Everyone has heard of rainforests, and has some idea of the sort of environment they entail. However, few people would be able to distinguish a cloud forest as an ecosystem, and few people understand their ecological and global importance as some of the most biodiverse and unique environments
on
the
planet.
These
environments are not only extremely beautiful, they also support high numbers of endemic species, many of which may not have yet even been identified. They are areas of natural wonder. However, they are also extremely fragile and changes in
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
49
et
Page
Aceves
climate caused by human activity, such as global warming and the expansion of the human population leading to increased
BUSH, M. B. 2002. Distributional change and conservation on the Andean flank: a palaeoecological perspective. Global Ecology and Biogeography, 11, 463-473.
agricultural dependence and increased urbanisation, are all hugely effecting the integrity of cloud forests. This could lead to massive wide scale extinction of huge numbers of species only found in cloud
BUTLER, R. 2012. Epiphytes [Online]. mongabay.com. Available: http://rainforests.mongabay.com/0405.htm [Accessed 31 July 2017 2017].
forests, and with this, the loss of many
protected, at both local and national scales, to neutralise climate change, the biggest threat to the cloud forests. Climate change due to human activity must be slowed down and stopped.
Bibliography ANCHUKAITIS, K. J. & EVANS, M. N. 2010. Tropical cloud forest climate variability and the demise of the Monteverde golden toad. Proceedings of the National Academy of Sciences of the United States of America, 107, 5036-5040.
ARMBRUSTER, P., HUTCHINSON, R. A. & COTGREAVE, P. 2002. Factors influencing community structure in a South American tank bromeliad fauna. Oikos, 96, 225-234.
BEIDERWIEDEN, E., WRZESINSKY, T. & KLEMM, O. 2005. Chemical characterization of fog and rain water collected at the eastern Andes cordillera. Hydrology and Earth System Sciences, 9, 185-191.
CAVELIER, J. & GOLDSTEIN, G. 1989. MIST AND FOG INTERCEPTION IN ELFIN CLOUD FORESTS IN COLOMBIA AND VENEZUELA. Journal of Tropical Ecology, 5, 309-322.
CORDERO, R. A. 1999. Ecophysiology of Cecropia schreberiana saplings in two wind regimes in an elfin cloud forest: growth, gas exchange, architecture and stem biomechanics. Tree Physiology, 19, 153-163.
DALY, G. L., LEI, Y. D., TEIXEIRA, C., MUIR, D. C. G., CASTILLO, L. E. & WANIA, F. 2007. Accumulation of currentuse pesticides in neotropical montane forests. Environmental Science & Technology, 41, 1118-1123.
ENRIQUEZ, S., DUARTE, C. M. & SANDJENSEN, K. 1993. PATTERNS IN DECOMPOSITION RATES AMONG PHOTOSYNTHETIC ORGANISMS - THE
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
50
ways in which cloud forests can be
CACH-PEREZ, M. J., ANDRADE, J. L., CHILPA-GALVAN, N., TAMAYO-CHIM, M., ORELLANA, R. & REYES-GARCIA, C. 2013. Climatic and structural factors influencing epiphytic bromeliad community assemblage along a gradient of water-limited environments in the Yucatan Peninsula, Mexico. Tropical Conservation Science, 6, 283-302.
Page
potential drugs and therapies. There are
FOSTER, P. 2001. The potential negative impacts of global climate change on tropical montane cloud forests. EarthScience Reviews, 55, 73-106.
GASNER, M. R., JANKOWSKI, J. E., CIECKA, A. L., KYLE, K. O. & RABENOLD, K. N. 2010. Projecting the local impacts of climate change on a Central American montane avian community. Biological Conservation, 143, 1250-1258.
GAWORECKI, M. 2015. New reserves in Colombia protect endangered species in a ‘Pleistocene refuge’ [Online]. US: Mongabay. [Accessed 12 August 2017].
HALLMANN, C. A., FOPPEN, R. P. B., VAN TURNHOUT, C. A. M., DE KROON, H. & JONGEJANS, E. 2014. Declines in insectivorous birds are associated with high neonicotinoid concentrations. Nature, 511, 341-+.
KOESTER, N., KREFT, H., NIEDER, J. & BARTHLOTT, W. 2013. Range size and climatic niche correlate with the vulnerability of epiphytes to human land use in the tropics. Journal of Biogeography, 40, 963-976.
KOSTER, N., NIEDER, J. & BARTHLOTT, W. 2011. Effect of Host Tree Traits on Epiphyte Diversity in Natural and Anthropogenic Habitats in Ecuador. Biotropica, 43, 685-694.
LEO, M. 1995. THE IMPORTANCE OF TROPICAL MONTANE CLOUD FOREST FOR PRESERVING VERTEBRATE ENDEMISM IN PERU - THE RIOABISEO-NATIONAL-PARK AS A CASE STUDY. Tropical Montane Cloud Forests, 110, 198-211.
LI, P. Y., WANG, G. L., FU, G. & LU, C. G. 2016. On spatiotemporal characteristics of sea fog occurrence over the Northern Atlantic from 1909 to 2008. Journal of Ocean University of China, 15, 958-966.
HEO, K. Y., HA, K. J., MAHRT, L. & SHIM, J. S. 2010. Comparison of advection and steam fogs: From direct observation over the sea. Atmospheric Research, 98, 426-437.
LIPS, K. R. 1998. Decline of a tropical montane amphibian fauna. Conservation Biology, 12, 106-117.
HOLDER, C. D. 2004. Rainfall interception and fog precipitation in a tropical montane cloud forest of Guatemala. Forest Ecology and Management, 190, 373-384.
MURRIETA-GALINDO, R., PARRAOLEA, G., GONZALEZ-ROMERO, A., LOPEZ-BARRERA, F. & VREDENBURG, V. T. 2014. Detection of Batrachochytrium dendrobatidis in amphibians inhabiting
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
51
FEARNSIDE, P. 2004. Are climate change impacts already affecting tropical forest biomass? Global Environmental Change, 14, 299-302.
KESSLER, M. 2001. Maximum plantcommunity endemism at intermediate intensities of anthropogenic disturbance in Bolivian montane forests. Conservation Biology, 15, 634-641.
Page
IMPORTANCE OF DETRITUS C-N-P CONTENT. Oecologia, 94, 457-471.
MYERS, N., MITTERMEIER, R. A., MITTERMEIER, C. G., DA FONSECA, G. A. B. & KENT, J. 2000. Biodiversity hotspots for conservation priorities. Nature, 403, 853-858.
PARMESAN, C. 2006. Ecological and evolutionary responses to recent climate change. Annual Review of Ecology Evolution and Systematics. Palo Alto: Annual Reviews.
PEH, K. S. H., SOH, M. C. K., SODHI, N. S., LAUREANCE, W. F., JEFRI ONG, D. & CLEMENTS, R. 2011. Up in the Clouds: Is Sustainable Use of Tropical Montane Cloud Forests Possible in Malaysia? BioScience, 61, 27-38.
POORTER, L., KWANT, R., HERNANDEZ, R., MEDINA, E. & WERGER, M. J. A. 2000. Leaf optical properties in Venezuelan cloud forest trees. Tree Physiology, 20, 519-526.
POUNDS, J. A., FOGDEN, M. P. L. & CAMPBELL, J. H. 1999. Biological response to climate change on a tropical mountain. Nature, 398, 611-615.
SCHOLL, M., EUGSTER, W. & BURKARD, R. 2011. Understanding the role of fog in forest hydrology: stable isotopes as tools for determining input and partitioning of cloud water in montane forests. Hydrological Processes, 25, 353366.
SETZER, M. C., MORIARITY, D. M., LAWTON, R. O., SETZER, W. N., GENTRY, G. A. & HABER, W. A. 2003. Phytomedicinal potential of tropical cloudforest plants from Monteverde, Costa Rica. Revista De Biologia Tropical, 51, 647-673.
SETZER, W. N. 2011. Drugs from the Cloudforest: The Search for New Medicines from Monteverde, Costa Rica. Natural Product Communications, 6, 1549-1558.
SHUNTHIRASINGHAM, C., GOUIN, T., LEI, Y. D., RUEPERT, C., CASTILLO, L. E. & WANIA, F. 2011. CURRENT-USE PESTICIDE TRANSPORT TO COSTA RICA'S HIGH-ALTITUDE TROPICAL CLOUD FOREST. Environmental Toxicology and Chemistry, 30, 2709-2717.
SMALL, A., MARTIN, T. G., KITCHING, R. L. & WONG, K. M. 2004. Contribution of tree species to the biodiversity of a 1 ha Old World rainforest in Brunei, Borneo. Biodiversity and Conservation, 13, 20672088.
Page
RICHARDSON, B. A., RICHARDSON, M. J., SCATENA, F. N. & MCDOWELL, W. H. 2000. Effects of nutrient availability and other elevational changes on bromeliad populations and their invertebrate communities in a humid tropical forest in Puerto Rico. Journal of Tropical Ecology, 16, 167-188.
RICHARDSON, M. J., RICHARDSON, B. A. & SRIVASTAVA, D. S. 2015. The Stability of Invertebrate Communities in Bromeliad Phytotelmata in a Rain Forest Subject to Hurricanes. Biotropica, 47, 201207.
52
cloud forests and coffee agroecosystems in central Veracruz, Mexico. European Journal of Wildlife Research, 60, 431-439.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
SODHI, N. E., PAUL. 2012. Conservation Biology for All, United States, Oxford University Press.
SOETHE, N., LEHMANN, J. & ENGELS, C. 2008. Nutrient availability at different altitudes in a tropical montane forest in Ecuador. Journal of Tropical Ecology, 24, 397-406.
STADTMÃœLLER, T. 1987. Cloud Forests in the Humid Tropics, A Bibliographic Review, Costa Rica, The United Nations University Press.
WILLIAMS-LINERA, G. 2002. Tree species richness complementarity, disturbance and fragmentation in a Mexican tropical montane cloud forest. Biodiversity and Conservation, 11, 18251843.
WILSON, S. J. & RHEMTULLA, J. M. 2016. Acceleration and novelty: community restoration speeds recovery and transforms species composition in Andean cloud forest. Ecological Applications, 26, 203-218.
TOLEDO-ACEVES, T., GARCIAFRANCO, J. G., WILLIAMS-LINERA, G., MACMILLAN, K. & GALLARDOHERNANDEZ, C. 2014. Significance of remnant cloud forest fragments as reservoirs of tree and epiphytic bromeliad diversity. Tropical Conservation Science, 7, 240-253.
TOLEDO-ACEVES, T., MEAVE, J. A., GONZALEZ-ESPINOSA, M. & RAMIREZMARCIAL, N. 2011. Tropical montane cloud forests: Current threats and opportunities for their conservation and sustainable management in Mexico. Journal of Environmental Management, 92, 974-981.
Page
VON CAEMMERER, S. & BAKER, N. 2007. The biology of transpiration. From guard cells to globe. Plant Physiology, 143, 3-3.
53
TRENBERTH, K. E. 2012. Framing the way to relate climate extremes to climate change. Climatic Change, 115, 283-290.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
The science and politics of rewilding Aramish Fatima Faculty of Biology, Medicine and Health, The University of Manchester, U.K.
Introduction Trends in human population demographic have shown exponential growth in the past few centuries (Haub, 2012). As human populations soar, so do the detrimental effects that they have on our environment (Mckinney,2002). Due to widespread human intervention and increasing urbanisation, deforestation and habitat degradation remain a major global concern. Disruption of the natural ecological processes has led to the eradication of the majority of the megafauna on all the continents. To combat this, biologists and ecologists are constantly working to devise new conservation strategies, the latest one being rewilding. Rewilding is a plastic term (Lorimer et al, 2015) and can include a variety of ideas. In general, re-wilding aims to diversify ecological habitats and enrich ecosystems through controlled reintroduction of apex predators, or in some cases major herbivores, that may or may not have inhabited the region in the past. The main theory behind rewilding is that through top-down
There are several different approaches within the boundaries of rewilding that different ecologists refer to: Trophic rewilding uses the concept of top-down trophic interactions and aims to enrich animal and plant diversity by establishing megafauna. Translocation rewilding involves the reintroduction of species that are thought to be missing from an ecosystem, to re-establish ecological processes. Pleistocene rewilding introduces substitute for megafauna that was present in the area in the Pleistocene and has gone extinct (taxon substitution). For example, the introduction of the giant tortoise to the Mauritian and Galapagos islands. Passive rewilding has the minimum amount of human interference and comprises of management of abandoned marginal land to restore
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
54
‘Rewilding’ is a relatively new and controversial concept in the field of conservation. It encompasses the idea of re-establishing extinct megafauna back into their native ecosystems. In this article, I have looked at the bigger picture and the possible effects this rewilding can have.
interactions occurring in trophic cascades, carnivores will have a dampening effect on herbivory, leading to a more diverse plant population. This will further lead to the influx of several other species that depend on plants, for example, insects, birds etc, as more niches will become available. Trophic cascades occur when apex predators or keystone species alter the predation risk or behaviour of a lower level species in a food web and indirectly cause a change in the level of herbivory.
Page
Abstract
Rewilding does not solely include the (re)introduction of large carnivores but can also refer to the practice of establishing top herbivores in an ecosystem. Mega-herbivores play a key role in recycling nutrients and help in seed dispersal as they are primary consumers in the food web and rely on plants as the main source of their diet. Their droppings are rich in urea and nitrogen, which are both organic fertilizers, thus creating a bio-cycle that benefits both the animal and the plants in the long term. The stomping and trampling of the ground by large herbivores also keeps the number of weeds low, further enhancing plant diversity. Research into this is underway at the Pleistocene Park in Siberia where five different large herbivore species (horses, moose, bison, ox, and reindeer) have been reintroduced in a 16000-hectare enclosure to test these predictions (Donlan,2006).
Science has a huge role in understanding all the interlinking functions taking place in a food webs and interactions leading to trophic cascades. On the other hand, the study of dynamic food webs and ecosystems through rewilding can provide further insight into their functioning and lay down basis for future ecological theories and discoveries. Rewilding can be viewed as being a cheaper form of conservation especially when it comes to practices like naturalistic grazing and passive rewilding which have limited human and resource investments. Diversification and the establishment of green corridors will boost the economy of the region by bringing in tourism and
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
55
Discussion
Page
ecosystem functioning. One approach suggests that to have a balanced ecosystem, there needs to exist ecological landscapes with wellconnected corridors, that allow interactions between different populations and gene flow. This will supposedly help increase or maintain biodiversity by creating a more stable ecosystem. This approach is sometimes referred to as the three C’s: “Cores, Corridors, and Carnivores” (Foreman, 2004). The flagship example of rewilding using the three Cs approach is the reintroduction of the Grey wolves in Yellowstone national park during the mid 1990s which proves to be one of the biggest success stories in trophic rewilding. The last wolves were extirpated from the park back in 1926 and since had remained absent from the locality. Due to the absence of the wolves, elk populations soared which had a negative effect on the plants and trees due to overgrazing, deciduous trees like aspen and cottonwood suffering the most. After the reintroduction, research on growth of aspen, willow, and cottonwood in recent years suggests that wolves have initiated a growth in tree populations (Dobson,2014). Indirectly, wolves may also be causing increases in bison, beaver, and bird populations. “Apex predators suppress species irruptions both directly and indirectly. Direct predation affects the species that the apex predator hunts whereas indirect effects occur when the reduction in the hunted species increases the abundance – and associated interactive strength – of other species” (Dobson, 2014).
Although at first glance rewilding seems like a good solution for restoring biodiversity, it has many underlying problems. One of the biggest issues the opponents raise is the level of uncertainty in any experiment carried out on rewilding. It is argued that there is no solid proof for the existence of trophic cascades, as there are several confounding factors not taken into consideration, for example, in the case of the Yellowstone wolves, the elk populations might be changing due to environmental factors such as weather,
There may be unexpected interactions or effects, even where a species is reintroduced into a system in which it was formerly a part. If herbivores are reintroduced without their historic predators, then major changes in vegetation composition and structure may follow, which may not always be positive. The experiments done by Robert T. Paine illustrate how the removal of a single keystone species (starfish in this case) can disrupt the entire ecosystem. There are other problems associated with introducing a
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
56
disease, drought etc. Experimenting with such a broad phenomenon can prove to be very difficult since one cannot simply remove a species from an ecosystem to gauge its effects as it would not be ethical. Most of the information about trophic cascades is derived from studying past extinction events and their impact on ecosystems. Experiments may also not be very reliable due to the difficulties faced in quantifying and measuring results, and any replication is not realistically possible. Food webs are extremely complex structures with numerous interspecies interactions occurring within them. Consequently, it is very difficult to establish if there are top down or bottom up interactions taking place. Top down control has a number of assumptions that may not be practically applicable, for example, although, Ripple and Beschta acknowledge that both variation in weather and multiple sources of predation were possible drivers of deer populations, yet they attribute variation in deer abundance to predation by a single species of carnivore, mountain lions. (Ford, 2015)
Page
more employment opportunities for the locals. The change in their economic conditions may encourage the locals to view rewilding more favourably. Rewilding may also be the key to the climate change issues plaguing the world, as it is essentially restoring the ecosystem back to what it was before human intervention. Such an ecosystem will be more resistant to environmental catastrophes like flooding, erosion etc. Through rewilding, we can also hope to educate and spread awareness to people about the devastating effects habitat destruction and species extinction can have on the ecosystem and the people who occupy it. This can potentially bring people closer to nature and as Marc Bekoff put it, “rewild their hearts�. Introducing large carnivores can keep herbivoury down which is detrimental to farmers as it can affect agriculture. It can also keep the number of invasive species down especially in the case of Australia by releasing dingoes. Rewilding may also bring regions and countries together to restore their ecosystems as nature does not see national boundaries.
Rewilding strategies should differ from one place to another depending on the individual social, political, environmental, financial and ethical needs of the area. There needs to be a compromise between rewilding ideals and what is practically implementable. In rewilding experiments, better risk to reward and cost-benefit analysis need to be performed. For instance, the lynx will be a better choice for reintroduction in England than the wolf since it is a lesser threat to people but can also help curb the problem of roe deer at the same time. In conclusion, for rewilding to gain a stronghold in conservation biology, more empirical data and evidence for trophic cascades need to be collected.
References Bekoff, M. (2014). Rewilding Hearts. New World Library.
Our
Corlett, R. (2016). Restoration, Reintroduction, and Rewilding in a Changing World. Trends in Ecology & Evolution, 31(6), pp.453-462. Dobson, A. (2014). Yellowstone Wolves and the Forces That Structure Natural Systems. PLoS Biology, 12(12), p.e1002025. Donlan, Berger, Bock, Bock, Burney, Estes, Foreman, Martin, Roemer, Smith, Soulé and Greene (2006). Pleistocene Rewilding: An Optimistic Agenda for
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
57
Rewilding as a conservation strategy has been met with very mixed reviews, where some starry-eyed conversationalists welcomed it with open arms, the traditional farming community and the politicians looked at it as a potential threat to their peaceful lives. The biggest disapproval was met from the farmers who were naturally against the introduction of any predators around their farmlands. They feared that the predators might prey on their livestock and cattle which is their only source of income. Farmers are also reluctant to take any financial compensation for their dead livestock as they would much rather live according to their traditional values. Bigger carnivores can also be a potential threat to human life, especially young children. Governments are very reluctant to change their land use policies for a conservation strategy that they are sceptical about. Certain politicians and the media are very opinionated and
vocal about their views about rewilding, for example, a recent article by Melissa Kite (2015) termed rewilding as “yet another outbreak of class warfare”. Rewilding programmes are also rejected by the local people as they are considered too “foreign”, with a very little concern for their welfare.
Page
non-native species in an area, for example, risk of spreading disease (which happened in bison populations reintroduced in a Danish forest which had a rich ‘worm fauna’), low genetic variability and higher competition for resources. Donor populations also suffer especially if the species is already endangered and the reintroduction is not successful. Species taken from underprivileged landmasses like Africa and transported to Europe for example can mean drainage of funding from less developed countries. One area of considerable concern is to do with the fact, that rewilding can take valuable funding opportunities from other areas of conservation.
Twenty-First Century Conservation. The American Naturalist, 168(5), p.660.
Pereira, H. (2015). Rewilding european landscapes. Cham [u.a]: Springer.
Foreman, D. (2013). Rewilding North America. [United States]: Island Press.
Ripple, W. and Beschta, R. (2012). Trophic cascades in Yellowstone: The first 15years after wolf reintroduction. Biological Conservation, 145(1), pp.205-213.
George Monbiot. (2017). A Manifesto for Rewilding the World. [online] Available at:http://www.monbiot.com/2013/05/27/a -manifesto-for-rewilding-the-world/ [Accessed 8 Mar. 2018]. Halliday, J. and Parveen, N. (2017). Plan to return the lynx splits friends and families in Kielder Forest community. [online] the Guardian. Available at: https://www.theguardian.com/uknews/2017/feb/03/plan-to-introduce-lynxto-kielder-forest-angers-farmers [Accessed 8 Mar. 2018]. Kite, M., Leith, S., Dalrymple, T. and Akeroyd, J. (2017). Rewilding: the left’s latest crazy, dangerous idea | The Spectator. [online] The Spectator. Available at: https://www.spectator.co.uk/2016/09/themissing-lynx/ [Accessed 8 Mar. 2018].
Svenning, J., Pedersen, P., Donlan, C., Ejrnæs, R., Faurby, S., Galetti, M., Hansen, D., Sandel, B., Sandom, C., Terborgh, J. and Vera, F. (2015). Science for a wilder Anthropocene: Synthesis and future directions for trophic rewilding research. Wallach, A., Ripple, W. and Carroll, S. (2015). Novel trophic cascades: apex predators enable coexistence. Trends in Ecology & Evolution, 30(3), pp.146-153.
Lorimer, J., Sandom, C., Jepson, P., Doughty, C., Barua, M. and Kirby, K. (2018). Rewilding: Science, Practice, and Politics. McKINNEY, M. (2017). Urbanization, Biodiversity, and Conservation. Nogués-Bravo, D., Simberloff, D., Rahbek, C. and Sanders, N. (2016). Rewilding is the new Pandora’s box in conservation. Current Biology, 26(3), pp. R87-R91.
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58
Palmer, M., Fukuyama, F. and Relman, D. (2015). A more systematic approach to biological risk. Science, 350(6267), pp.1471-1473.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
The naked mole rat: Ugly little monster or beautiful supermodel‌ for human diseases? Flora Matilda Jefferson Tickell Faculty of Biology, Medicine and Health, The University of Manchester
of tumours. Furthermore, naked mole
Abstract
rats have a similar longevity quotient to eusocial
humans which makes them a good
burrowing mammal, has for many years
model for the progression of diseases
been of great interest to the scientific
such as Alzheimer’s. Understanding the
community due to the unique molecular
mechanisms employed by naked mole
mechanisms of their cellular makeup.
rats could give an insight into new
Firstly, due to the neonatal structure of
treatments and therapies for a range of
their neurones, naked mole rats are
diseases, including stroke, heart attack,
highly resistant to hypoxic conditions,
and cancer.
The
naked
mole
rat,
a
and it has been shown that their brains They
also
show
insensitivity to thermal and chemical pain stimulation, thanks to the unique functional connectivity of C-fibres to the spinal column and the structure of NMDA receptors on their nociceptors, making them of interest in the study of new pain-relief drugs. Naked mole rats have shown no natural incidence of cancer due to the molecular structure of the hyaluronan in their extracellular matrix, which allows cells to stop proliferating
at
relatively
low
cell
densities and prevents the progression
Introduction The naked mole rat (NMR) is a small eusocial rodent of the Bathyergidae family found in the Horn of Africa, which for many years has been of interest to the scientific community. Weighing just 35g, NMRs can live to over 28 years (Gorbunova et al., 2009) in giant underground colonies of up to 300 individuals, all under the command of a single queen (Husson et al., 2015). The queen and a few select males are the only individuals in the colony allowed to breed,
while
the
other
NMRs
are
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
59
environments.
Page
make a full recovery from low oxygen
burrow. The sealed burrows of NMRs
tolerance
of
the
naked mole rat
(Larson et al., 2012) can run for 3km
Ischemia
underground,
their
mammals, ischemia occurs when blood
external incisors to dig for the tubers on
vessels are blocked, preventing the flow
which they feed (Husson et al., 2015).
of blood to certain tissues in the body
Though unique in many regards, recent
and therefore limiting oxygen supply to
discoveries
molecular
cells. Oxygen is necessary for ATP
mechanisms utilised by NMR cells show
production, which is needed to establish
potential for this rodent to act as a
ion concentration gradients within the
model organism for a variety of human
cell
diseases. NMRs are remarkable; despite
Imbalances
their small size they can live to over 30
gradients are dangerous; for example,
years in laboratory conditions, and show
stroke damage is caused by reperfusion
little or no ageing over this time until
and the excitotoxicity of the intracellular
directly before their death (Gorbunova
calcium overload response (Pisani et al.,
et al., 2009). NMRs are also unique as
2004). High calcium levels within cells
they show insensitivity to both hypoxic
result in the over-expression of calpains,
environments and acidic or chemical
which break down cellular proteins and
stimuli, unlike other rodents. Above all,
lead to apoptosis or necrosis (Larson et
no natural cancer has been found in any
al., 2012, Vanlangenakker et al., 2008).
naked mole rat (Seluanov et al., 2013),
Necrosis is particularly damaging to
even when tumour cells or oncogenes are
tissues as the enzymes released from the
transferred into NMR cells (Hornsby et
dying
al., 2010). The mechanisms applied by
inflammatory immune esponse, harming
the NMR to resist ageing, pain and
neighbouring
anoxic conditions can be compared to
Vanlangenakker
and
human
Furthermore, high levels of intracellular
processes of disease at a greater level.
calcium result in massive glutamate
Eventually, certain aspects of NMR
release
molecular makeup could be applied to
overstimulating the NMDA glutamate
humans for the development of new
receptors on the postsynaptic membrane
treatments and therapies.
which
used
and
on
to
NMRs
use
the
understand
and
(James
its
consequences.
PhilipNeubauer, in
cells
ion
stimulate cells
into
and
concentration
a
strong
al.,
the
uncontrollably
potentials
1998).
(Rothwell, et
further
In
2003, 2008).
synapse,
fire incite
action brain
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
60
foraging for food and cleaning the
Hypoxia
Page
workers, caring for the queen’s offspring,
damage (Pisani et al., 2004). As with the
NMRs live in crowded burrows with low
brain,
extremely
oxygen availability and high carbon
oxygenic organ, and the rhythmicity of
dioxide levels (Park Thomas J.Larson,
the myocytes is controlled by neuronal
2009, Park et al., 2014). Not only are
inputs from the sinoatrial node (Tham et
they able to survive, they thrive in these
al., 2015). Neuronal inputs are highly
conditions due to unique molecular
coordinated, and a branching network of
mechanisms. Firstly, to make the most
fibres ensures that the atrium contracts
of the oxygen available, NMRs have low
first, followed by the ventricles after a
oxygen
short delay. A block in the coronary
incredibly low metabolic rates (Park
arteries results in the same processes of
Thomas J.Larson, 2009). Furthermore,
cell death as seen in stroke (Tham et al.,
the haemoglobin in their blood has a
2015).
contract
high affinity for oxygen allowing them to
asynchronously as the dying cells create
make the most of what is available
an
produces
(Park Thomas J.Larson, 2009) and to
autonomous action potentials due to the
protect against high CO2 levels the blood
incorrect handling of calcium (Tham et
exhibits properties which act as a buffer
al., 2015). These spontaneous action
against low pH by neutralising excess
potentials mean that the heart cannot
carbonic acid (Park Thomas J.Larson,
contract efficiently or with coordination,
2009, Johansen et al., 1976). However,
resulting in heart attack due to loss of
what makes NMRs unique and so
cardiac
crucial in the study of human ischemia
the
heart
The
ectopic
is
muscle focus
output
2015)(Choices,
an
that
(Tham
2017).
et
Most
al.,
ischemic
is
that
consumption
they
exhibit
levels
due
normal
to
brain
attacks can ultimately lead to death,
function during low oxygen exposure
which makes the study of how to
and complete neural recovery after
prevent the damage caused by ischemia
exposure to almost anoxic conditions. In
extremely important, especially in terms
2009, Larson and Park exposed NMRs
of stroke treatment or prevention.
and mice brain hippocampal slices to varying oxygen concentrations in vitro. Action potentials were stimulated in evoked responses. It was found that
tolerance
when compared to mice, the neurones of
applications. hypoxia
and
their
It
seems
resistance
therapeutic likely
evolved
that
because
NMRs continued firing signals much longer
into
periods
of
anoxia.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Page
Naked mole rat mechanisms of ischemic
61
neurones and micropipettes recorded the
Furthermore, at 10% O2, the mice
structure of certain NMDA receptors
showed reduced response to the induced
found in the hippocampus (Larson et al.,
action potentials until there was no
2012), which have GluN2D subunits
signal recorded from the neurones and
that can block the entry of calcium into
no
neurones
recovery
exhibited.
However,
under
low
Other
oxygen
although NMRs showed a considerable
concentrations.
reduction in the signals during hypoxia,
mammalian NMDA receptors such as
on the application of normal levels of O2
GluN2A and GluN2B are lost in the
the neurones made a full recovery.
adult NMRs; they only retain the
Larson and Park hypothesise that the
neonatal subunits that give them the
high tolerance to hypoxia may be due to
advantage of surviving in low oxygen
“slow or arrested” activity of the brain
environments (Larson et al., 2012) and
which prevents the spread of damage
therefore resistance against the stroke-
(Park Thomas J.Larson, 2009), and an
like effects of hypoxia. Not only do
understanding of the mechanisms used
neurones with GluN2D subunits repel
by NMRs to achieve this during periods
calcium, which is toxic when in high
of low O2 may help to identify new
concentrations, they also have slower
strategies for treating stroke in humans.
depolarisation
events
embryonic
meaning
that
neuronal damage cannot occur quickly (Larson et al., 2012). Though quickly In mice, during periods of reduced
lost after birth, humans are born with
oxygen
causes
this ability and therefore the genes for
irreversible cell damage that mirrors the
GluN2A expression are present in the
damage
excitotoxicity
human genome. If these genes were to
following a stroke in human patients
be up-regulated by drugs in adults this
(Larson et al., 2012). As explained
could have the potential to prevent the
above, NMRs do not show these effects.
damage caused by stroke, and could
The brains of NMRs are protected by a
even be applied to ischemic heart or
phenomenon called ‘delayed neuronal
liver disease.
by
depolarisation’ which is observed in human neonates but is lost soon after birth (Larson et al., 2012); NMRs are some of the only animals to retain this ability into adulthood. Delayed neuronal depolarisation is due to the unique
Hypoxic resistance and its role in cancer. Tumours are formed through a process of abnormal cell proliferation which is so rapid that blood vessel formation is not similarly sustained. Therefore, the cores of tumours are often
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
62
caused
hypoxia
Page
availability,
hypoxic (Park Jun YongChoi, 2017).
hypoxia
However, cancerous cells are resistant to
(Johnson et al., 2003). Therefore, an
hypoxia as they do not use oxidative
organism
phosphorylation
hypoxia, such as the NMR, may also
Instead,
to
mutations
generate in
ATP.
mitochondrial
show
advances with
tumorigenesis
high
increased
resistance resistance
to to
enzymes allow a metabolic switch to
tumorigenesis making this pathway a
occur,
potential model for cancer resistance.
with
glucose
metabolism
favouring glycolysis even in aerobic environments
(Hanahan,
2011).
Although this is a highly inefficient way
Naked Mole Rats and their
to
resistance to cancer
generate
ATP,
this
pathway
is
advantageous to the cancerous cell as the glycolytic intermediates are used to
Cell
generate the amino acids, fatty acids
regulation in cancers. In humans, cell
and nucleic acids required for rapid
densities and proliferation rates are
proliferation
controlled through a balance of growth
of
and
produces lactic acid, which is pumped
Robert Ahanahan, 2000). The main
out of the cell causing extracellular
control on the mitotic cycle occurs
acidification. Extracellular acidification
during the Gap 1 phase when abundant
facilitates the matrix metalloproteinases
nutrients and a lack of cell damage
secreted
during
allow pRB proteins to suppress E2F
metastasis and is also involved in
proteins, permitting the transcription of
inhibiting
surveillance.
genes required to move into the S phase
This is known as the Warburg Effect
of mitosis and start DNA replication (RJ
and is stimulated by the activation of
and
the
HIF1-alpha
conditions, for example if there is DNA
early in tumorigenesis (Hanahan, 2011).
damage, limited nutrients or cellular
Hypoxia
sustained
infection, antigrowth signals such as
YongChoi,
Cyclin D inhibit pRB proteins and block
2017), which further exacerbates the
the cell cycle (RJ and Y, 2013), stopping
effects of the angiogenesis caused by
proliferation.
growth
proliferation of cancers is due to the
migratory
immune
transcription also
angiogenesis
Ahanahan, addition
2000) to
cell
factor causes
(Park
factors
cells
Jun
(Weinburg
2013).
The
In
(Weinburg
unfavourable
uncontrolled
cell
in
avoidance of antigrowth signals and
metastasis,
their high apoptotic resistance, allowing
meaning
promoting
Robert
Y,
signals
loss
Furthermore, this form of ATP synthesis
by
antigrowth
its
that
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
63
2011).
and
Page
(Hanahan,
proliferation
malignancy and migration into new
the p53 and pRb tumour suppressor
tissues (Weinburg Robert Ahanahan,
pathways,
2000). Vertebrate cells show a variety of
(Gorbunova et al., 2009). Both p53 and
different mechanisms to avoid cancer.
pRb
For example, ‘senescence’ acts as a
(Syrjanen et al., 1999) and if they are
strong
absent
tumour
suppressor
by
are or
or
by
tumour
targeting suppressor
inactivated
by
p27 genes
mutation,
irreversibly arresting the mitotic cycle
excessive cell proliferation can occur. In
(Lynch, 2006, Campisi, 2001). Contact
normal cells, p53 levels increase after
inhibition, the ability of cells to sense
cell damage, leading to P21 expression
each
stop
which arrests cell growth by blocking
proliferating, is another mechanism of
entry into the S-phase of the mitotic
mitotic
al.,
cycle. However, 50% of tumours show a
2009),(Seluanov et al., 2013), and cells
mutated form of p53 which is unable to
that don't exhibit this are capable of
recruit the expression of p21, meaning
forming tumours. Cancers are evident in
the
almost all vertebrates, however, an
(Syrjanen et al., 1999). One level of
incidence of naturally occurring cancer
protection NMRs have against cancer is
in a naked mole rat has never been
extreme p53 expression even when cells
reported (Buffenstein, 2008).
exhibit no cell damage, contributing to
other’s
proximity
arrest
and
(Gorbunova
et
cell
cycle
cannot
be
arrested
ECI (Buffenstein et al., 2012). Early contact inhibition is also exhibited due Naked mole rats and their resistance to
to the unique form of hyaluronan (HA)
cancer through ECI. In culture, NMR
NMRs
fibroblast cells have not been seen to
component of the extracellular matrix
produce tumours (Gorbunova et al.,
(Seluanov et al., 2013), is a large
2009). They proliferate extremely slowly
negatively
and contact inhibition occurs at cell
secreted by fibroblasts (Toole, 2004)
densities three times lower than those
which interacts with glycosaminoglycan
seen in mouse cultures (Gorbunova et
(Day et al., 1996). It is important in
al., 2009), a capability of NMR cells that
holding connective tissues together and
has
contact
its ability to retain water means it keeps
inhibition’ (ECI) (Gorbunova et al.,
joints lubricated (Toole, 2004). However,
2009). ECI blocks the proliferation of
it also plays a role in inflammation and
cells before they reach a high density
self-recognition of tumorous cells by the
and is thought to be triggered by using
immune
‘early
charged
system
an
important
polysaccharide
(Toole,
2004).
In
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
64
termed
HA,
Page
been
possess.
cancers, HA is linked to metastasis
levels of HA are linked with malignant
because, by binding to cell membrane
cancers and the growth of tumours,
receptors, it plays a role in cell adhesion
NMRs are very different as their HA is
and motility (Frankel DanielRankin,
linked
2016)
malignancy
why
is
(Frankel
DanielRankin,
2016). The main physical difference
Furthermore,
between human and NMR HA is that
healthy cells that encounter tumorous
NMR HA is secreted at a very high
cells are forced to overproduce HA to
molecular mass, five times greater than
further aid metastasis (Toole, 2004,
the molecular mass of human HA
Weaver, 2004). In malignant tumours of
(Seluanov et al., 2013, Turley et al.,
breast and ovarian cancers, high levels
2015).
of HA are linked with low survival rates
involved in the synthesis of different
(Kosma et al., 2000, Toole, 2004) and it
forms of HA (Stern et al., 2001),
has been shown that decreasing HA
including HAS2, which is normally
levels in cancerous cells of prostate
expressed exclusively in the mammalian
cancers can lead to a reduction in
embryo. NMRs, however, show HAS2
tumour size (McCarthy et al., 2002), as
over-expression
can
individuals,
al., 2002).
increasing
enzymes
malignant
it
not
tumours
(Heldin et
in
be
resistance,
that
the
production
break
down
of HA
There
are
different
even
along
hyaluronidase
in
with
that
genes
adult
a
form
degrades
of HA
(hyaluronidases)(Heldin et al., 2002,
extremely slowly, allowing HA to build
Stern et al., 2002). Hyaluronidases are
up in the tissues (Seluanov et al., 2013).
found in high levels in many tumours,
Although it is hypothesised that HAS2
perhaps due to the immune system’s
primarily encodes skin elasticity (which
attempt to fight cancer by reducing high
is advantageous for burrow-dwelling
levels of HA. However, it has been
organisms) it is also involved in cancer
postulated
resistance, albeit secondarily. The link
that
hyaluronidases
may
actually cause cancer by breaking HA
between
into small fragments which have been
demonstrated when NMR cells with
shown to cause angiogenesis, furthering
knocked-down HAS2 were transferred
tumour progression (Soloway et al.,
into mice, resulting in the grafted cells
2002)(Lokeshwar et al., 2003).
becoming tumorous. NMR cells that
Naked
mole
mechanisms
rats that
have
unique
encode
cancer
resistance. While in human cells high
HAS2
overexpressed
and
HYAL2
cancer
(the
was
HAS2-
degrading enzyme) which were grafted into
mice
also
became
tumorous
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
65
overproduced
may
cancer
Page
which
with
(Seluanov et al., 2013). The importance
failure of mitosis - which results in the
of HA in the control of cell proliferation
cells freezing in their mitotic cycle and
was shown when a rapid form of
eventually dying (Hornsby et al., 2010).
hyaluronidase was applied to cultures of
This gives the NMR an extra level of
NMR fibroblasts in vitro; when the
resistance against cancer.
hyaluronidase was applied, the early contact inhibition shown normally by NMR cells was not apparent, and cells
Naked mole rats would make good
proliferated unchecked. However, when
models for human cancer treatments.
the hyaluronidase was removed, cells in
Despite showing fundamentally distinct
the
providing
anti-cancer mechanisms and completely
evidence of early contact inhibition
different cancer occurrence rates than
restarting (Seluanov et al., 2013). HA is,
humans, mice are used as the standard
therefore, a key component of the early
model in the study of human cancers
contact inhibition exhibited by NMR
(Gorbunova et al., 2009). A naked mole
(Day et al., 1996), and current literature
rat would be a better model for human
suggests that it blocks the spread of
cancer because, despite the negligible
cancerous cells by forming a cage-like
cancer occurrence rate (Treuting et al.,
structure around the cells (Seluanov et
2016), the systems utilised by NMRs
al., 2013).
and humans to combat excessive cell
Although NMRs have a negligible cancer occurrence rate (de Jesus and Blasco, 2013), interestingly, they do express oncogenes. Oncogenes are genes that normally cause cancer when either overexpressed or mutated. It has been shown that when expressed in human cells, the oncogenes which are found in NMRs can cause human cells to become cancerous
(Hornsby
et
al.,
2010).
However, if expressed in the cells of NMRs, these genes do not lead to cancer. Instead, mutations in oncogenes such
as
the
NMR
oncogene
SV40
Tag/Ras cause the cells to enter crisis - a
proliferation are more similar than those
mechanisms
used
by
mice
(Gorbunova et al., 2009). Furthermore, NMRs and humans also have similar longevity quotients (i.e. they both have long lives for their relative mass) which would allow the development of cancers over a longer lifetime to be effectively studied (Buffenstein, 2008). Where mice rely on telomerase as an anti-cancer mechanism (de Jesus and Blasco, 2013), both NMRs and humans use a form of contact
inhibition
to
prevent
uncontrolled cell division. As mentioned above, the early contact inhibition in
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
66
began dying,
Page
culture
NMRs is a more effective mechanism
Currently,
against tumour development than the
aspirins are the most common form of
contact inhibition seen in humans. As it
pain relief provided to patients but these
is the HAS2 form of HA in NMRs that
often are not 100% effective, or they may
provides resistance, if this gene could be
have strong side effects that should be
expressed
avoided
in
humans
it
could
be
drugs
such
(Golar,
opiates
2011).
Pain
and
is
effective against cancer occurrence. This
experienced when free nerve ending,
would require gene knock-in therapies of
‘nociceptors’,
high
(Mense, 2009) which can be caused by
precision,
perhaps
using
the
signal
tissue
thermal
CRISPR/Cas9 system. However, even if
mechanical,
successful this gene therapy may not be
stimuli. Inflamed tissues affected even
effective because the bigger the body
mildly in these ways release chemicals
size of an organism, the higher the
that activate the nociceptors and cause
cancer risk (Gorbunova et al., 2009).
‘hyperalgesia’, an increased sensitivity
Importantly, HA has been identified as
to pain (Park et al., 2008). Although
a drug target against cancer while an
different nerves are innervated after
understanding of how NMR cells enter
different types of pain stimulation,
crisis when oncogenes are expressed
generally
could help to develop novel strategies
through the stimulation of myelinated
and gene targets for cancer treatments
A-delta
(Gorbunova et al., 2009).
Substance P (Mense, 2009) and is sharp
the
first
axons
or
damage
pain
by
chemical
caused
glutamate
is and
and fast. The second pain is slower, long-lasting and duller than the first
Naked mole rats and their
pain, mediated through the stimulation
resistance to pain
of unmyelinated C-fibres (Mense, 2009).
Pain in is an essential part of life,
inflammation,
designed to protect bodies from damage
disease
and to alert us to disease. However, it is
understanding of how it works and (in
extremely distressing. Pain is a natural
terms of the NMR) why sometimes it
by-product of many diseases and an
doesn’t,
unavoidable aspect of the treatment of
development of new drugs for pain relief
many
and inflammation.
or
cancer
example
in
and
could
key
component
infection,
be
useful
so
in
of an
the
therapies.
Page
operations
for
a
67
diseases,
Pain response is strongly linked with
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Mechanisms employed by naked mole
same way as when strong heat is
rats that confer high resistance to pain
applied and for this reason it is used to
could be used as a model in the
study the pain pathways elicited by high
development of new drugs. As a result of
heats on animals. NMRs show pain
being crowded and poorly ventilated,
resistance
NMR
CO2
mechanisms. The first way in which
of
NMRs have a unique experience of the
carbonic acid to form on moist tissues of
physical world around them is that their
NMRs such as the eyes and the nose
skin lacks C-fibres that respond to
(Park et al., 2008). However, NMRs
substance P (Park et al., 2003). They
show no behavioural response to this
also have very few Aβ fibres or Merkel’s
(Park et al., 2008), nor do they make any
fibres in their dermis (Park et al., 2003)
effort to avoid acidic fumes (Thomas,
and lack neuropeptides, which means
2012). This is because NMRs do not
that
show hyperalgesia in reaction to heat or
innervated in their skin (Park et al.,
capsaicin, which is normally mediated
2003). These factors alone make them
by TRPV1 ion channels (Rosenbaum et
very
al., 2004). The application of capsaicin (a
relatives and probably came around as
compound found in chillies) to skin
an adaptation of living in crowded
results in nerve endings firing in the
underground burrows(Park et al., 2008).
allowing
high films
nociceptors
different
several
are
from
not
their
different
easily
closest
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
68
concentrations,
have
to
Page
burrows
due
In 2008, a study by Park et al. was
hyperalgesia is mediated by the TRPV1
published showing how the responses of
cation channel which is activated when
NMRs and mice to certain stimuli differ.
TrkA receptors bind neuronal growth
To test the difference between the
factor (Lewin et al., 2016). However, in
sensitivity of NMRs and mice, each had
NMRs, the TrkA receptors do not have
an acidic saline solution or capsaicin
the ability to sensitise TRPV1 channels
solution injected into their paw. The
due to three changes in their amino acid
duration of behavioural response – paw
sequence
licking – was measured. After injection
Furthermore, the C-fibres of NMRs
of acid or capsaicin, the mice spent on
associated with capsaicin sensitivity
average 210 and 28 seconds respectively
interact with the spinal cord in a
licking their
However, NMRs
different way from most other C-fibres
showed no paw licking behaviour after
as they connect with the spinal cord in
the injection of either stimulant (Park et
the deep lamina of the dorsal neurones
al., 2008). The complete insensitivity of
(Park et al., 2008) (see figure). This
NMRs
capsaicin
unusual form of functional connectivity
stimulant is achieved by the utilisation
results in the C-fibres being unable to
of
was
stimulate pain pathways into the brain,
suggested that the acid insensitivity
and therefore no pain response is
arises from the altered structure of the
observed (Park et al., 2008). Diseases
sodium
NMRs.
and their treatments are often linked
heightened
with high levels of pain and nowadays
stimulation under acidic conditions, in
the majority of pain relieving drugs are
the presence of acid these channels are
based on aspirin or opiate compounds
physically blocked by protons and so
and are not risk-free; many have side
shut down the nociceptors necessary to
effects or cause malaise when taken
elicit a pain response (Gary, 2012).
Park et al., 2008too frequently or at too
Conversely, nociceptors and C-fibres are
high doses (Golar, 2011). Understanding
stimulated in response to capsaicin and
the pain desensitisation mechanisms
heat. However, as seen in the results of
used by NMRs could provide new drug
the experiments stated above, although
targets for the safe and more efficient
there is stimulation of the nociceptors,
treatment of pain.
to
either
different
Rather
paw.
or
mechanisms.
channel than
acid
NaV1.7 showing
It
in
(Lewin
et
al.,
2016).
vertebrates,
capsaicin-activated-
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
Page
the brain (Lewin et al., 2016). In
69
the pain impulse is not transmitted to
Naked mole rats and their resistance to ageing
Naked mole rats show exceptionally slow ageing. Humans are different from
The mechanisms of ageing. Ageing is
other animals as they do not fit into the
defined by the irreversible physical and
model of maximum species life span
functional changes the body exhibits
(Buffenstein, 2005). This life span model
over a lifetime. It is seen in every
shows the correlation between the mass
animal and irrevocably ends with death.
of a mammal and its life expectancy, the
As the body ages, it becomes physically
trend being that smaller animals have
weaker
against
shorter lifespans than larger animals
pathogens. Reproductive success falls,
(Buffenstein, 2005). Humans have an
and the body becomes more susceptible
extremely long lifespan despite being
to damage and disease (Buffenstein,
rather a small species; humans outlive
2008); people and animals don't die from
even elephants. NMRs, however, exhibit
being old, they die from the diseases
a similarly large longevity quotient; they
accumulated due to the fragility of old
can live up to 30 years, despite weighing
age. One of the main ways in which
only 35g (Buffenstein, 2005). Due to
mammalian bodies age over time is due
relatively recent advances in healthcare,
to the effects of oxidative stress (Husson
pharmaceuticals
et al., 2015). Oxidative stress is caused
unsurprising that humans live to such
robust
in the mitochondria of cells; as they age
and
diet,
it
is
an old age, and have a longevity
they produce damaging reactive oxygen
quotient of 5.1 (Buffenstein, 2005).
species in a negative feedback loop (Ma
However, NMRs do not benefit from
et al., 1998) until ultimately there is an
lifestyle augmentation, they simply have
imbalance in reactive oxygen species
naturally acquired a longevity quotient
and free radicals (Aggarwal et al., 2010).
of 5.0(Buffenstein, 2005) and the ability
This oxidative stress not only causes the
to live nine times longer than rodents of
damage in cells that is linked to ageing
a similar body mass (Buffenstein, 2008,
but
severe
O'Connor et al., 2002). Furthermore,
inflammation associated with a variety
NMRs show few signs of ageing over
of diseases, from cancer to diabetes
their 30-odd years, remaining in good
(Aggarwal et al., 2010). Age and disease
health throughout (Buffenstein, 2005)
come hand in hand and for this reason it
with breeding females bearing young
is important to study for the elevation of
well into the late stages of their lives
the problems associated with ageing.
(Buffenstein, 2008). Their lack of ageing
also
results
in
the
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
70
less
Page
and
is also exhibited as they show no
oxidative stress seen in NMRs the
changes in basal metabolic rate, bone
damage incurred would be phenomenal.
density or body fat percentage over time
NMRs, however, show little malaise due
(Gorbunova et al., 2009). Instead, they
to high levels of cysteine residues in
accumulate these characteristics very
proteins within their cells (Andziak et
rapidly immediately before their death
al., 2006). These residues act as a buffer
(Husson
against oxidative damage, physically
2015).
These
characteristics mean that NMRs exhibit
absorbing
a
‘negligible
protecting the rest of the cell (Husson et
senescence’ (Buffenstein, 2008), which
al., 2015). Further protection is provided
describes the extremely slow ageing of
by
species
and
(Andziak et al., 2006) and high levels of
capabilities remain constant for the
heat shock proteins in NMR cells, giving
majority of
the animal’s life(Finch,
proteins resistance against unfolding
1991). Due to their longevity quotient
(Chen et al., 2013, Perez et al., 2009).
being so similar to human’s and their
Here it is important to note that heat
apparent lack of ageing, NMRs are an
shock proteins are often linked to
ideal model for human ageing, which is
incidences of cancer, particularly in
important to study due to its strong
melanomas where heat shock proteins
links with human disease (Buffenstein,
are over-expressed, so high levels of heat
2005).
shock proteins in NMRs and their lack
very
robust
whose
form
of
phenotype
Mechanisms of the slow ageing of naked mole rats. The exceptional life span of NMRs might be due to its eusocial life, or perhaps the high levels of inbreeding seen in colonies, which can result in low genetic
change
over
generations
(Buffenstein, 2005). However what is most striking is that NMRs have high levels of oxidative damage from a young age (Andziak et al., 2006). This is very different from what is seen in humans, which accumulate oxidative damage over many years (Ma et al., 1998). If humans
experienced
the
level
of
the
damage
low
and
levels
of
therefore
antioxidants
of cancer occurrence is of interest (Chen et al., 2013). Lastly, the cell membranes of NMRs have a low peroxidation index which further declines with age giving the
cells
extra
resilience
against
oxidative damage (Buffenstein et al., 2013b).
An
understanding
of
these
processes makes NMRs a good model for human ageing. The most significant ability of NMRs - the lack of reaction to high levels of oxidative stress - has implications in humans, where oxidative stress causes inflammation linked with diabetes, heart disease and importantly
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
71
al.,
Page
et
cancer,
as tissue inflammation can
protective molecular arrangements in
trigger a healthy cell to become a
the
brain
and
to
explore
why
tumour cell (Aggarwal et al., 2010). The
Alzheimer’s is more prevalent in some
use of NMR models to find ways of
individuals than others. Furthermore,
reducing the levels of inflammation
due to the long life of the rodent, if
caused by oxidative stress could lead to
Alzheimer’s could be expressed in a
new cancer therapies.
NMR it would be a good model for the study of the disease progression over a lifetime. Nowadays, mice or rat models
Naked mole rats and their
are used, both of which have short life
resistance to Alzheimer’s
spans, so the development of the disease over
a
lifetime
cannot
be
fully
Alzheimer’s affects more than 520,000
understood. A greater understanding
people in the UK, is associated with
could
memory loss and confusion, and is the
development
leading cause of dementia (K, 2016).
protective measures against Alzheimer’s
Alzheimer's disease is caused by a build-
(Buffenstein et al., 2013a).
also
be of
implicated new
in
therapies
the or
up of beta-amyloid peptide plaques in the brain that ultimately leads to they
express both amyloid-beta and Tau, a protein
involved
polymerisation,
no
in signs
plaque of
the
neurodegeneration linked to Alzheimer’s has ever been observed in a NMR (Buffenstein et al., 2013a). It is thought that this is because of a single change in the
amino
acid
sequence
of
NMR
amyloid beta (Buffenstein et al., 2013a). Furthermore, high levels of Neuregulin 1 expressed in NMR brain tissue protect brain activity from oxidative stress (Buffenstein et al., 2013a). Due to these protective mechanisms, NMRs would provide
a
useful
model
to
study
Conclusion The naked mole rat is a unique species in so many ways. Not only does it exhibit
extraordinary
eusocial
behaviour, it also has many molecular structures and mechanisms that protect it from a range of diseases. Some of the diseases NMRs are resistant to are the leading causes of mortality in humans in the Western world, such as cancer and stroke. For each disease the NMR shows resistance to, more than one mechanism is utilised; resistance is not conferred simply from one pathway. For example, the fact that NMRs have exhibited no form of cancer is due to unique forms of
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
72
Although
Page
neurodegeneration.
HA, early contact inhibition, resistance against hypoxia and protection against oxidative damage. Furthermore, NMRs can be used as a model for pain tolerance and for ageing, both of which
BUFFENSTEIN, R., CACCAMO, A., ODDO, S., OSMULSKI, P. A., GACZYNSKA, M., MEDINA, D. X. & EDREY, Y. H. 2013a. Amyloid beta and the longest-lived rodent: The naked mole-rat as a model for natural protection from Alzheimer's disease. Neurobiology of Aging, 34, 2352-2360.
are irrevocably linked with disease. Therefore, understanding how NMRs these
diseases
provides
an
opportunity to compare human and NMR mechanisms, giving researchers a greater
understanding
of
human
diseases and insights into pathways to target in new therapies and treatments.
Bibliography AGGARWAL, B. B., CHATURVEDI, M. M., GUPTA, S. C. & REUTER, S. 2010. Oxidative stress, inflammation, and cancer: How are they linked? Free Radical Biology and Medicine, 49, 1603-1616.
ANDZIAK, B., O’CONNOR, T, P., QI, W., DEWAAL, E, M., PIERCE, A., CHAUDHURI, A, R., VAN REMMEN, H., BUFFENSTEIN, R. 2006. High oxidative damage levels in the longest-living rodent, the naked mole-rat. New York: Aging Cell, 5, 463-471.
BUFFENSTEIN, R. 2005. The naked molerat: A new long-living model for human aging research. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 60, 1369-1377.
CAMPISI, J. 2001. Cellular senescence as a tumor-suppressor mechanism. Trends in Cell Biology, 11, S27-S31.
CHEN, L., ZHANG, Y. & YANG, Z. 2013. Investigation of anti-cancer mechanisms by comparative analysis of naked mole rat and rat. BMC Systems Biology, 7.
CHOICES, N. H. S. 2017. Coronary heart disease.
DAY, A. J., CAMPBELL, I. D., INAGAKI, F. M., HATANAKA, H., PARKAR, A. A., MORTON, C. J. & KOHDA, D. 1996. Solution structure of the link module: A Hyaluronan-Binding domain involved in Extracellular matrix stability and cell migration. Cell, 86, 767-775.
DE JESUS, B. B. & BLASCO, M. A. 2013. Telomerase at the intersection of cancer and aging. Trends in Genetics, 29, 513-520.
Page
BUFFENSTEIN, R. 2008. Negligible senescence in the longest living rodent, the naked mole-rat: Insights from a successfully aging species. Journal of Comparative Physiology B, 178, 439-445.
BUFFENSTEIN, R., YANG, T., ANDZIAK, B. & LEWIS, K. N. 2013b. The naked molerat response to Oxidative stress: Just deal with it. Antioxidants & Redox Signaling, 19, 1388-1399.
73
resist
BUFFENSTEIN, R., HORNSBY, P. J., MELE, J. & LEWIS, K. N. 2012. Stress resistance in the naked mole-rat: The bare essentials ? A Mini-Review. Gerontology, 58, 453-462.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
FINCH, C. E. E. 1991. Longevity, senescence, and the genome, University of Chicago Press.
FRANKEL DANIELRANKIN, K. S. 2016. Hyaluronan in cancer - from the naked mole rat to nanoparticle therapy. Soft Matter, 12, 3841-3848.
GARY, L. 2012. The molecular basis of behavioural acid insensitivity in the African naked mole-rat. Frontiers in Behavioral Neuroscience, 6.
GOLAR, S. K. 2011. Use and understanding of analgesics (painkillers) by Aston university students. Bioscience Horizons, 4, 71-78.
GORBUNOVA, V., CATANIA, K. C., MAO, Z., BOZZELLA, M., FEIGENSON, M., AZPURUA, J., HINE, C. & SELUANOV, A. 2009. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proceedings of the National Academy of Sciences, 106, 19352-19357.
HUSSON, Z., SCHUHMACHER, L.-N. & SMITH, E. S. J. 2015. The naked mole-rat as an animal model in biomedical research: Current perspectives. Open Access Animal Physiology, 137-137.
JAMES PHILIPNEUBAUER, R. 1998. Cerebral oxygenation and the recoverable brain. Neurological Research, 20, S33-S36.
JOHANSEN, K., LYKKEBOE, G., WEBER, R., MALOIY, G, M., 1976. Blood respiratory properties in the naked mole rat Heterocephalus glaber, a mammal of low body temperature. Respiration Physiology, 28, 303-314.
JOHNSON, R. S., DOZIER, S. J. & GODA, N. 2003. HIF-1 in cell cycle regulation, Apoptosis, and tumor progression. Antioxidants & Redox Signaling, 5, 467-473.
K, G. 2016. Alzheimer's Disease [Online]. Available: www.alzheimers.org.uk/info/20007/types_of_ dementia/2/alzheimers_disease [Accessed 5 March 2017].
HANAHAN, D. W., R 2011. HHallmarks of Cancer: The Next Generation. Cell, 144. KOSMA, V.-M., HIRVIKOSKI, P.,
AGREN, U., TAMMI, M., PARKKINEN, J., TAMMI, R. & AUVINEN, P. I. 2000. Hyaluronan in Peritumoral Stroma and malignant cells associates with breast cancer spreading and predicts survival. The American Journal of Pathology, 156, 529536.
LARSON, J., PARK, T. J. & PETERSON, B. L. 2012. Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals. Neuroscience Letters, 506, 342-345.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
74
HORNSBY, P. J., BUFFENSTEIN, R., WU, Y., MELE, J. & LIANG, S. 2010. Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell, 9, 626635.
M., R.,
Page
HELDIN, P., RUBIN, K., RAHMANIAN, M. & JACOBSON, A. 2002. Expression of hyaluronan synthase 2 or hyaluronidase 1 differentially affect the growth rate of transplantable colon carcinoma cell tumors. International Journal of Cancer, 102, 212219.
ESKELINEN, JOHANSSON,
2016. Hypofunctional TrkA accounts for the absence of pain Sensitization in the African naked mole-rat. Cell Reports, 17, 748-758.
LOKESHWAR, V. B., FISHER, P., WEED, D. T., GOODWIN, W. J., SCHROEDER, G. L. & FRANZMANN, E. J. 2003. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors. International Journal of Cancer, 106, 438-445.
LYNCH, M. D. 2006. How does cellular Senescence prevent cancer? DNA and Cell Biology, 25, 69-78.
MA, Y.-S., PANG, C.-Y., LEE, H.-C., LU, C.Y. & WEI, Y.-H. 1998. Oxidative damage and mutation to Mitochondrial DNA and age-dependent decline of Mitochondrial respiratory Functiona. Annals of the New York Academy of Sciences, 854, 155-170.
MCCARTHY, J. B., WILSON, C. M. & SIMPSON, M. A. 2002. Inhibition of prostate tumor cell Hyaluronan synthesis Impairs Subcutaneous growth and Vascularization in Immunocompromised mice. The American Journal of Pathology, 161, 849-857.
MENSE, S. 2009. Algesic agents exciting muscle nociceptors. Experimental Brain Research, 196, 89-100.
O'CONNOR, T. P., LEE, A., JARVIS, J. U. M. & BUFFENSTEIN, R. 2002. Prolonged longevity in naked mole-rats: age-related changes in metabolism, body composition and gastrointestinal function. Comparative
PARK JUN YONGCHOI, S. H. 2017. Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference. Cancer Cell International, 17.
PARK THOMAS J.LARSON, J. 2009. Extreme hypoxia tolerance of naked molerat brain. NeuroReport, 20, 1634-1637.
PARK, T. J., COMER, C., CAROL, A., LU, Y., HONG, H. S. & RICE, F. L. 2003. Somatosensory organization and Behavior in naked mole-rats: II. Peripheral structures, innervation, and selective lack of neuropeptides associated with thermoregulation and pain. Journal of Comparative Neurology, 465, 104-120.
PARK, T. J., LU, Y., JUETTNER, R., SMITH, E. S. J., HU, J., BRAND, A., WETZEL, C., MILENKOVIC, N., ERDMANN, B., HEPPENSTALL, P. A., LAURITO, C. E., WILSON, S. P. & LEWIN, G. R. 2008. Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber). Plos Biology, 6, 156-170.
PARK, T. J., MILTON, S. L., FOLKOW, L. P., DREW, K. L. & LARSON, J. 2014. No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates. Journal of Experimental Biology, 217, 1024-1039.
PEREZ, V. I., BUFFENSTEIN, R., MASAMSETTI, V., LEONARD, S., SALMON, A. B., MELE, J., ANDZIAK, B., YANG, T., EDREY, Y., FRIGUET, B., WARD, W., RICHARDSON, A. & CHAUDHURI, A. 2009. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
75
M., SMITH, E. S. J. & OMERBASIC, D.
Page
LEWIN, G. R., SELBACH, M., FAULKES, C. G., REZNICK, J., BENNETT, N. C., EIGENBROD, O., HOMFELD, J., MORONI,
Biochemistry and Physiology a-Molecular and Integrative Physiology, 133, 835-842.
DURONIO R, J. & XIONG, Y. 2013. Signaling pathways that control cell proliferation. Cold Spring Harbor Laboratory, 5.
ROSENBAUM, T., GORDON-SHAAG, A., MUNARI, M. & GORDON, S. E. 2004. Ca2+/calmodulin modulates TRPV1 activation by capsaicin. Journal of General Physiology, 123, 53-62.
ROTHWELL, N. 2003. Interleukin-1 and neuronal injury: Mechanisms, modification, and therapeutic potential. Brain, Behavior, and Immunity, 17, 152-157.
SELUANOV, A., GORBUNOVA, V., NEVO, E., MAO, Z., ABLAEVA, J., MYAKISHEVREMPEL, M., VAIDYA, A., HINE, C., AZPURUA, J. & TIAN, X. 2013. Highmolecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature, 499, 346-349.
SOLOWAY, M. S., MARKOWITZ, S., ROSE, L., WATSON, R., DUNCAN, R. C., POSEY, J. T., HAUTMANN, S. H., SELZER, M. G., SCHROEDER, G. L. & LOKESHWAR, V. B. 2002. Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic acid-hyaluronidase and BTA-Stat tests. Cancer, 95, 61-72.
STERN, R., FORMBY, B., CSOKA, A. B., FROST, G. I. & SHUSTER, S. 2002. Hyaluronidase reduces human breast cancer
STERN, R., FROST, G. I. & CSOKA, A. B. 2001. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biology, 20, 499-508.
SYRJANEN,
K.,
SAARIKOSKI,
S.,
JUHOLA, M., PUOLAKKA, J., HONGXIU, J., KOSMA, V. M. & ANTTILA, M. A. 1999. P21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. British Journal of Cancer, 79, 1870-1878.
THAM, Y. K., BERNARDO, B. C., OOI, J. Y. Y., WEEKS, K. L. & MCMULLEN, J. R. 2015. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Archives of Toxicology, 89, 1401-1438.
THOMAS, P. 2012. Blunted behavioral and Trigeminal responses to Acidic fumes in the African naked mole-rat. Frontiers in Behavioral Neuroscience, 6.
TOOLE, B. P. 2004. Hyaluronan: From extracellular glue to pericellular cue. Nature Reviews Cancer, 4, 528-539. TREUTING, P. M., KINSEL, M. J., KERNS, K., CHINNADURAI, S. K., WALSH, T. F., WARD, J. M. & DELANEY, M. A. 2016. Initial case reports of cancer in naked molerats (Heterocephalus glaber). Veterinary Pathology, 53, 691-696.
TURLEY, E. A., MCCARTHY, J. B., SCHWERTFEGER, K. L., LEE, H.-G. & COWMAN, M. K. 2015. The content and size of Hyaluronan in biological fluids and tissues. Frontiers in Immunology, 6.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018
76
PISANI, A., BONSI, P. & CALABRESI, P. 2004. Calcium signaling and neuronal vulnerability to ischemia in the striatum. Cell Calcium, 36, 277-284.
xenografts in SCID mice. International Journal of Cancer, 102, 192-197.
Page
living rodent, the naked mole-rat. Proceedings of the National Academy of Sciences, 106, 3059–3064.
VANLANGENAKKER, N., VANDEN BERGHE, T., KRYSKO, D. V., FESTJENS, N. & VANDENABEELE, P. 2008. Molecular mechanisms and pathophysiology of necrotic cell death. Current Molecular Medicine, 8, 207-220.
WEAVER, V. M. 2004. Watch thy neighbor: Cancer is a communal affair. Journal of Cell Science, 117, 1287-1290.
Page
77
WEINBURG ROBERT AHANAHAN, D. 2000. The Hallmarks of Cancer. Cell, 100, 57-70.
Manchester Undergraduate Journal of Biological Sciences | vol. 2, March 2018