Volume 2 issue 1 - MUJBSc

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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).

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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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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.

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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.

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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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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.

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