Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration...

GRD Journals- Global Research and Development Journal for Engineering | Volume 6 | Issue 6 | May 2021 ISSN- 2455-5703

Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration Resulting into Pathogenesis of Parkinson's Disease Janhavi Dhore Student Department of Biological & Bio System Engineering Ajeenkya DY Patil University, Pune

Abstract Parkinson's disease (PD) is the second most common neurodegenerative (ND) disorder known to occur all over the world, mostly in the old-aged people. PD is recognised as an α-Synucleinopathy which features the accumulation of ND protein that is alphasynuclein (α-syn), in neuronal and glial cells. It is acquainted with poor neuronal signalling and impaired neurons mainly in the substantia nigra part of the central nervous system. Aggregates of α-synuclein were discovered to be the building blocks of Lewy Bodies(LB), which is the pathological hallmark of PD. Lewy pathology accumulation resulted in progressive loss of dopaminergic neurons in the substantia nigra pars compacta. On the other hand, astrocytes are major and most abundant glial cell type in the brain, which are found to degrade α-syn to some extent. They can transfer the protein from one neuron to other directly or through Tunneling nanotubes (TNTs). However, due to over accumulation, over longer period of time it results into mitochondrial abnormalities and detrimental cellular processes in astrocytes therefore leading to glial cell death. The abnormal ND protein accumulation is identified to be caused due to a range of external and internal factors which dysrupts the intracellular and extracellular activities of neuronal cells. Specifically, α-syn aggregates might have been triggered by various factors such as: aging, environmental-oxidative stress or inflammation, genetic mutations and polymorphisms, impaired cellular processes like protein clearance systems (UPS and ALP) and dysfunction of mitochondrial and lysosomal pathways. α-Syn portrays a vicious cycle wherein damage to proteasomal and lysosomal systems could cause α-Syn to accumulate, and thereby increased levels of α-Syn could inhibit the proteasome and lysosomal systems, ultimately leading to the formation of oligomers and aggregates, which results into neurodegeneration and clinical dysfunction. It causes mitochondrial and lysosomal dysfunction which eventually leads to cell death and neurodegeneration leading to PD pathogenesis.

Keywords- Parkinson's Disease, Alpha-Synuclein, Lewy Body, Astrocytes, Neurodegeneration, Mitochondrial Dysfunction, Lysosomal Dysfunction

I. INTRODUCTION Studies delineate that diverse neurodegenerative (ND) disorders comprising of Parkinson's disease (PD), Alzheimer's disease (AD), Huntington’s and prion diseases, frontotemporal dementia and motor neuron diseases which are considered to be caused due to accumulation and deposition of various misfolded, abnormal aggregates of protein like amyloid-ß, tau, alpha-synuclein (α-syn).

[1], [2] The deposition of aberrant protein results into malfunctioning of neurons since it triggers mitochondrial dysfunction, disruption of autophagy and endo-lysosomal pathways which in turn leads to degeneration of dopaminergic neurons in the substantia nigra which advances towards the pathogenesis of PD. [1], [3], [4] Accumulation of pathologic α-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and, eventually, neuron death.

[5] Recapitulation of a ND cascade thus establishes a mechanistic link between transmission of pathologic α-syn and the cardinal features of PD.[6] A. Parkinson's Disease (PD) PD is the second most common neurodegenerative disorder known to occur all over the world, mostly in the old-aged people. [3] PD is an α-Synucleinopathy which features the accumulation of aggregated α-syn in neuronal and glial cells. [7], [8] PD is marked with symptoms such as tremors and weakness. The tremors occurring when a patient at rest had accompanying features of movement rigidity, slowed movements, a typical hunched posture, and very soft speech whereas a patient in action showed signs of weakness spasticity, and visual disturbance.[9] Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity, along with non-motoric symptoms like autonomic, cognitive, and psychiatric problems.[10] Moreover, clinical symptoms of PD demonstrate dysfunction of synapses as All rights reserved by www.grdjournals.com

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Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration Resulting into Pathogenesis of Parkinson's Disease (GRDJE/ Volume 6 / Issue 6 / 003)

one of the pathophysiological mechanism of the disease. [11] Recent clinical-pathological studies have put forward PD hallmarks as progressive neuronal loss. [3] Primarily neuron loss is thought to be major step in neurodegeneration in PD. In addition, synaptic disorder is caused due to accumulation of α-syn aggregates at the synapse leading to synaptic dysfunction is another major source for neurodegeneration. [11] However, increased levels of the normal protein itself can cause the disease at times. Through investigations, brains of PD patients are characterised by abundant α-syn neuronal inclusions, known as Lewy bodies (LB) and Lewy neurites, these are intracellular inclusions of insoluble α-syn fibrils that are known to cause enormous loss of midbrain dopamine neurons. [6], [12] Basically, aggregates of α-synuclein were discovered to be the building blocks of LBs, the pathological hallmark of PD. [13] Lewy pathology accumulation resulted in progressive loss of dopaminergic neurons in the substantia nigra pars compacta.[10] The current pathophysiological hypothesis for the disease mechanism of PD is that the loss of dopaminergic neurons results in the depletion of the neurotransmitter dopamine in the striatum, which in turn causes the motor impairment symptoms, as discussed primarily.[14] α-syn aggregates are neurotoxic and contribute towards PD progression in multiple ways. Recent studies have reported that misfolded α-syn can spread between neighbouring cells, with the help of astrocytes[15] and can cause neuronal cell death. [5] It suggests the intriguing possibility that transmission of pathologic α-syn plays a central role in PD pathogenesis and progression.

[10] Furthermore, α-syn generates aggregates which are particularly neurotoxic, associate with mitochondria and induce mitochondrial dysfunction.[16][15] α-Syn aggregation and mitochondrial dysfunction both contribute to the PD pathogenesis.[16] Since mitochondrial dysfunction is a key feature in PD progression, which is caused by disrupted mitochondrial respiration, decreased mitochondrial membrane potential, and impaired mitophagy in neuronal cells, [7], [8] thereby accumulation of α-syn aggregates plays a leading role in PD progression. On the other hand, genetic alterations and mutations are crucial factors in initiating the pathogenesis of PD. Two genes are clearly associated with the disease: α-syn (PARK1) and parkin (PARK2) [2], mutations in parkin led to Lewy body formation as seen in sporadic PD. [17] Autosomal dominant PD results in mutations in the α-syn gene and autosomal recessive PD is due to mutations in the parkin gene.[1] In familial PD, autosomal dominant α-syn gene mutations directly link α-syn dysfunction to disease causation.[4] B. Alpha-Synuclein (α-syn) α-syn is a 140 amino acid protein which is normally soluble and functions as presynaptic terminal protein as a chaperone to modulate the activity of the synaptic-vesicle fusion machinery, trafficking and endocytosis. [3], [13] Studies propose that α-syn also has an important role in endocytosis by mediating synaptic vesicle regeneration following a neuronal stimulation. [18] One of the genes that encodes α-syn is SNCA.[18] α-syn typically exists in a monomeric form however when present in excess it leads to formation of multimeric structures and aggregates, resulting into formation of lewy body(LB) eventually. Aggregates of α-syn are the main components of cytosolic eosinophilic Lewy body inclusions, which are found in afflicted central and peripheral nervous systems of PD patients, most abundant in the SNpc where selective dopamine (DA) neuron loss is greatest .[19] In addition, more certainly when α-syn is misfolded, the random coil of the NAC domain forms β-sheets, which participate in protofibril and fibril formation.[14] Importantly, genetic modification has effect on structural form of α-syn. Two mutations in α-syn (E46K, A53T) increase the oligomeric and fibrillar forms of α-syn, further highlighting the importance of the aggregation of α-syn in its toxicity.[14] Insoluble α-syn aggregates and fibrils with β-sheet secondary structure are a main constituents of LBs and seem to be neurotoxic.[18] During fibril formation, α-synuclein generates soluble intermediate aggregates, that are oligomers, which are particularly neurotoxic. For example, oligomeric α-syn has been shown to disrupt cellular membranes and induce mitochondrial dysfunction.[16], [15], [20] Toxic α-syn has previously been shown to cause mitochondrial morphology, increased mitochondrial fragmentation and affected mitophagy in neuronal cells.[15] Moreover, experimental evidence indicates that α-syn can transfer from cell to cell in various ways thereby contributing towards disease progression. [15] A study shows that accumulation of α-syn in cultured human cells selectively degenerates dopaminergic neurons in presence of DA but not non-dopaminergic neurons suggesting a selective toxicity of its accumulation. [21] C. Astrocytes and Alpha-Synuclein (α-syn) Astrocyte is the major and most abundant glial cell type in the brain, although it's exact role in PD progression is unclear. [15] Although, astrocytes do not degrade α-syn aggregates but they transfer it to healthy astrocytes through direct contact and tunneling nanotubes (TNTs). [15] α-syn deposits are also found in astrocytes in the advanced stages of PD. Recent experimental study delineated that the rapid and extensive uptake of α-syn oligomers in astrocytes, indicates that astrocytes carry out a crucial role in sequestering toxic α-syn from the extracellular space.[12] Initially, this uptake is advantageous as it prevents α-syn toxicity and PD progression to some extent proving to be neuroprotective in nature. [12] But in due course, when α-syn is stored in astrocytes for longer time period it eventually affects mitochondrial integrity leading to neurotoxicity. [12] Generally, α-syn accumulation in the astrocytes affects, disrupts their phagosomal-lysosomal machinery and induces mitochondrial damage. [15][12] α-syn oligomers colocalize with glial cells where particularly astrocytes internalise large amounts of protein, which is attempted to degrade via lysosomal pathway.[15] However due to overburdened protein than it's degrading capacity the remains of incompletely digested α-syn leave behind large intracellular deposits leading to mitochondrial abnormalities and detrimental cellular processes in astrocytes. [15]

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Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration Resulting into Pathogenesis of Parkinson's Disease (GRDJE/ Volume 6 / Issue 6 / 003)

D. Alpha-Synuclein (α-syn) Leading to Neurodegeneration The factors leading to aggregation of α-syn still remain to be elucidated, Cell and tissue senescence, environmental or genetic factors may contribute to promote the aggregation of physiological α-syn.[11] The excessive accumulation of α-syn disrupts intracellular trafficking, synaptic functions, endo-lysosomal functions and also causes oxidative stress, mitochondrial dysfunction and impairment of many more cellular processes. [13] E. Causes of Aggregate Formation Contributing to PD Pathogenesis According previous studies it has been put forward that α-syn aggregates might have been triggered by various factors such as: aging[13], environmental oxidative stress or inflammation, genetic mutations and polymorphisms, impaired cellular processes (like protein clearance systems, mitochondrial and lysosomal pathways). Increased levels of α-syn might arise as a consequence of damage or toxicity due to factors such as oxidative stress or inflammation that cause the protein to misfold and resist clearance.[22] Oxidative stress, toxins, and interaction with oxidized DA further increase the propensity of α-syn to aggregate and accumulate.

[3] The extracellularly released α-syn through exocytosis might have detrimental roles by inducing inflammation directly by acting as a chemoattractant that draws inflammatory microglia towards damaged neurons or by helping to spread PD pathology.[13] In sporadic cases of PD, increased levels of α-syn might occur as a consequence of impaired clearance of the protein.[22] There are various protein clearance systems functioning in PD namely: autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS) and defects in both of these systems have been detected in patients with sporadic PD.[22],[23] Environmental factors have potential to impair the protein clearance systems. There is evidence that α-syn aggregates can interfere with the function of the ubiquitin proteasome and lysosomal systems thereby further impairing clearance of the protein.[25] [22] UPS is responsible for a highly selective degradation of short-lived intracellular and plasma membrane proteins under basal metabolic conditions, as well as misfolded or damaged proteins in the cytosol, nucleus or endoplasmic reticulum which includes misfolded proteins such as α-syn.[24] Dysfunction of UPS results into accumulation of misfolded proteins have been strongly implicated in the pathogenesis of PD, which is supported by molecular genetic studies of PD-causing genes, including α-syn, parkin and UCHL1.[23] Another factor that is genetic mutation in α-syn (duplications, triplications, or point mutations) facilitate aggregate formation in neurons by impairing the cellular processes thereby affecting the exacerbation and progression of PD.[8] The identification of several genetic forms of PD has strongly implicated mitochondrial and lysosomal dysfunction as key cellular processes that contribute to PD pathogenesis.[18] Mutations in genes that encode for proteins involved in lysosomal function (glucosidase b acid [GBA]; scavenger receptor class B, member 2 [SCARB2]; ATP13A2) and proteasomal function (Parkin, ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]) are associated with, or are risk factors for, the development of PD.[22] These observations support the notion that impaired protein clearance assisted with genetic mutation or not could cause α-syn to accumulate and contribute to the development of PD.

Fig. 1: It depicts there are five factors that contribute towards α-Syn aggregates' accumulation. Aging; Environmental toxic factors such as oxidative stress and inflammation leads to α-Syn accumulation in two ways- directly causes toxicity and by resisting the protein clearance indirectly. In genetic factor arises due to point mutations, polymorphism, duplications, triplications in genes which code for α-Syn (like SNCA, parkin). It also affects by hampering the lysosomal and proteasomal functions via gene mutations in GBA, SCAR2,Parkin,UCH-L1.

Dysfunction of lysosomal and mitochondrial processes and impaired ALP and UPS systems cause α-Syn to accumulate and contribute to the development of PD. Vice-versa there is evidence that α-Syn aggregates can interfere with the impairment of these systems thereby further boosting the accumulation. [Red cross symbolises negatively affecting the mechanisms]

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Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration Resulting into Pathogenesis of Parkinson's Disease (GRDJE/ Volume 6 / Issue 6 / 003)

As a result, impaired protein clearance systems (UPS,ALS) and impaired cellular systemic processes (lysosomal and mitochondrial systemic functions) cause α-syn aggregates to accumulate. In return, this α-syn accumulation further weaken and worsen both the systems advancing its own production in addition. Therefore, it portrays to be a vicious cycle wherein damage to proteasomal and lysosomal systems could cause α-Syn to accumulate, and increased levels of α-Syn could inhibit the proteasome and lysosomal systems, ultimately leading to the formation of oligomers and aggregates, which results into neurodegeneration and clinical dysfunction.[26] F. Consequences of Accumulation of α-Syn at Synapse An excess of α-synuclein in the form of monomers, multimers or aggregates can disrupt intracellular trafficking and synaptic function and contributes to the formation of LBs. [13] It is most likely that the aggregation process starts at the pre-synapse.[11] Even the aggregation process itself and not just the deposition of aggregates can be harmful to neurons.[11] α-Syn usually localizes to synaptic vesicles and might modulate the pool of vesicles and vesicle docking with the membrane. [13] α-syn accumulates inappropriately and interferes, too robustly with the priming of synaptic vesicles, which leads to a decrease in the size of the pool of releasable vesicles.[13] The α-syn micro-aggregates influence vesicle trafficking and impair neurotransmitter release.[11] As a consequence, postsynaptic dendritic spines degenerate, and a loss of synaptic connections leading to post-synaptic degeneration, which results in clinical symptoms of neurodegeneration.[11] At the time at which the dendritic spines degenerate, the involved neurons may still be alive.[11] Neuronal cell death can occur at any time after the neurodegenerative process, which has been initiated by presynaptic α-syn micro-aggregation.[11] Intra-axonal α-syn accumulation occurs as part of Lewy pathology and may impair axonal transport functions as well.[11] On the other hand, formation of endogenous α-syn aggregates away from presynaptic terminals leads to selective alterations in synaptic proteins, compromises neuronal excitability and connectivity, and culminates in neuron death.[5] G. Cytosolic Dopamine (DA) and α-syn Accumulation Leads to Neuronal Death One of the latest investigations has proposed that the accumulation of α-syn with cytosolic oxidized dopamine (DA) has deleterious effects on mitochondria, lysosome and synapses which builds up oxidative stress in cell thereby heading into neurodegeneration, eventually resulting into cell death. Recent work has identified a pathway for cytosolic oxidized DA and α-syn accumulation due to dysfunction in synaptic vesicle endocytosis in human-derived dopaminergic neurons.[18] These α-syn oligomers notably affect mitochondrial function, endoplasmic reticulum (ER) ER–Golgi trafficking, protein degradation, and synaptic transmission, which induce neurodegeneration therefore this α-Synucleinopathy induces mitochondrial dysfunction, especially in the context of calcium homeostasis.[3][8] Mitochondria regulate calcium levels through interactions with ER.[8] In post mortem PD brains and animal models, overexpressed or mutant α-syn accumulate in the ER, thus impairing protein folding and evoking ER stress. [3] Abnormal α-syn accumulates in both the mitochondria and ER which stresses the ER to release too much calcium into mitochondria, the reaction can further inhibit mitochondrial function by impairing ATP production and increasing ROS production via mitochondrially mediated metabolism of cytosolic DA, which can lead to cell death.[18] [8]

Fig. 2: Cascade leading to neurodegeneration: α-syn accumulation initiated by mutation or overexpression causes dysfunction of ER and mitochondria directly and indirectly by producing oxidative environment due to excess of free radicals. It eventually exacerbates misfolded protein degradation by impairing ALP, UPS pathways, finally resulting into neuronal death.

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Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration Resulting into Pathogenesis of Parkinson's Disease (GRDJE/ Volume 6 / Issue 6 / 003)

In addition, α-syn is associated with another mitochondrial dynamics, such as the regulation of morphology (fission and fusion), axonal transport and mitophagy.[8] In one of the studies, overexpression of α-synuclein in dopamine neurons of the mouse mid- brain has been reported to impede mitophagy. [27] H. α-syn Affects Lysosomal Functions It has been shown that wild-type α-syn, but not the mutant α-syn, is selectively translocated into lysosomes for degradation by the Chaperone-mediated autophagy-(CMA) pathway [23], since mutant forms of the protein are prone to misfold [22]. The accumulated mutant α-syn and other substrates further perturb cellular homoeostasis and contribute to neuronal toxicity.[23] α-syn is also cleared by autophagy which is mediated by lysosomes, supports the hypothesis that impaired autophagic degradation of αsyn is an important mechanism of neurodegeneration in PD. [23] Lysosomal impairment increases the transfer of α-syn between cells. [29] Cell-to-cell transmission of aggregated α-syn accelerates Synucleinopathy.[8] Alternatively, α-syn accumulation disrupts Glucocerebrosidase (GCase) trafficking to lysosomes and decreases GCase activity, which may further exacerbate protein misfolding underlying GBA-associated PD Lewy body formation.[3] Supporting this, enhancing GCase activity has been shown to decrease α-syn accumulation and salvage lysosomal, mitochondrial, and neuronal dysfunction.[28] Functional loss of GCase activity due to GBA1 mutations have been shown to decrease lysosomal proteolysis, disrupt the ubiquitin-proteasome pathway, and interfere with autophagic processes, thereby further inducing α-syn accumulation and neuron toxicity in human midbrain neuron cultures.[32] α-syn assemblies have been previously shown to induce the rupture of lysosomes in vitro and lysosomal membrane permeation (LMP) has been reported in a mouse model of PD.[34] In addition, α-syn can contribute to lysosomal dysfunction, which may further involve defective proteolytic turnover of synaptic proteins and the accumulation of insoluble protein aggregates.[18] It has been found that if the lysosomal degradation machinery of even the innate immune cells has been overwhelmed by cell debris such as α-syn aggregates, micro- glia and other innate immune cells probably become over-activated and cause damage to neurons. [13] Therefore, there is interdependence between α-syn accumulation causing lysosomal dysfunction and vice-versa.

II. CONCLUSION PD pathogenesis is strongly driven by accumulation of ND pathologic protein that is α-syn, leading to selective decrease in synaptic proteins, progressive impairments in neuronal excitability and connectivity, cellular dysfunction and, eventually, neuron death, [5] more prominently in substantia nigra region in the brain. Although astrocytes are functionally known to degrade α-syn aggregates.

Generally, overburdened and prolonged α-syn accumulation in the astrocytes affects, disrupts their phagosomal-lysosomal machinery and induces mitochondrial damage, [15][12] leading to mitochondrial abnormalities and detrimental cellular processes.

Moreover, there are diversified and several factors that cause accumulation of α-syn aggregates. Environmental factors, aging, genetic causes such as multiple mutations and polymorphisms, crucial factors - impaired protein clearance systems and impaired cellular systemic processes are five main causes of α-syn accumulation. Impaired protein clearance systems and impaired cellular systemic processes lead to α-syn accumulation and increased α-syn levels further worsen the systems resulting into excessive aggregate accumulation proves an interdependent correlation between causes of accumulation and its resultant effects. Most importantly, α-syn aggregates lead to neurodegeneration in multiple ways by damaging a neuronal cell in more than one aspect.

The α-syn accumulation at synapse influence vesicle trafficking and impair neurotransmitter release causing loss of synaptic connections leading to post-synaptic degeneration, which eventually results into neuronal death. Furthermore, the accumulation of α-syn with cytosolic oxidized dopamine (DA) has deleterious effects on mitochondria, lysosome and synapses which builds up oxidative stress in cell thereby heading into neurodegeneration, eventually resulting into cell death. It is conceivable that the convergence of synaptic, mitochondrial, and lysosomal dysfunction may exacerbate cytosolic DA and α-syn accumulation and ultimately result in cell death in PD.[18] The relationship between mitochondria and α-syn is one of interconnection, the import of α-syn into mitochondria impairs a broad range of mitochondrial functions.[3] More specifically, α-syn overexpression or genetic mutation causes dysfunction of mitochondria, mitochondrial axonal transport decrease as ATP production decreases and ROS production increases, due to impaired mitochondrial-ER Ca2+ exchange at the mitochondria-associated membrane which causes neuronal death. [3] In addition this mitochondrial dysfunction also triggers α-syn accumulation which further impairs the protein clearance pathways (UPS, ALS dysfunction) resulting into failure of misfolded protein degradation which in turn leads to neuronal death. Moreover, turnover of synaptic proteins and the elimination of damaged mitochondria and oxidized DA by lysosomes via synaptic autophagy are critical in maintaining dopaminergic synapses. [18] Both mitochondria and endo-lysosomal dysfunction contribute to the development of α-syn pathology.[3] Lysosomal system which should ideally eliminate cell debris and ND protein such as α-syn, fails to function due to overwhelming accumulation of α-syn aggregates, which impairs lysosomal autophagy responses, decreases GCase activity and eventually results into neuronal death. Several partially-penetrant mutations of PD converge on cellular clearance pathways, this has been observed in several mechanistic studies that have linked lysosomal dysfunction to defective mitochondrial clearance and α-syn toxicity.[30] In conclusion, several factors contribute in α-syn accumulation which affect cellular processes in more than one way which leads to neurodegeneration, specifically leading towards PD pathogenesis.

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Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration Resulting into Pathogenesis of Parkinson's Disease (GRDJE/ Volume 6 / Issue 6 / 003)

ABBREVIATIONS Neurodegenerative (ND) Parkinson's disease (PD) Alzheimer's disease (AD) Alpha-synuclein (α-syn) Lewy bodies (LB) Tunneling nanotubes (TNTs) Dopamine (DA) Induce Reactive Oxidative Species (ROS) Autophagy-Lysosome Pathway (ALP) Ubiquitin-Proteasome System (UPS).

Chaperone-Mediated Autophagy (CMA) Endoplasmic Reticulum (ER) Glucocerebrosidase (GCase) Lysosomal Membrane Permeation (LMP) Calcium Ions (Ca2+)

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