Template:Short description Template:Cs1 config Template:Infobox gene Alpha-synuclein (aSyn) is a protein that in humans is encoded by the SNCA gene.<ref name="ghrsnca">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters.<ref name="Bonini_2005" /><ref name="Chandra_2005" />
Alpha-synuclein is abundant in the brain, with smaller amounts present in the heart, muscles, and other tissues. Within the brain, it is primarily localized to the axon terminals of presynaptic neurons.<ref name="ghrsnca" /> There, it interacts with phospholipids<ref>Template:Cite journal</ref> and other proteins.<ref name="ghrsnca" /><ref name="Sun_2019" /><ref>Template:Cite journal</ref> Presynaptic terminals release neurotransmitters from specialized compartments called synaptic vesicles, a process essential for neuronal communication and normal brain function.<ref name="ghrsnca" />
In Parkinson's disease and related synucleinopathies, abnormal, insoluble forms of alpha-synuclein accumulate within neurons as inclusions known as Lewy bodies.<ref>Template:Cite journal</ref> Mutations in the SNCA gene are linked to familial forms of Parkinson's disease. During the process of seeded nucleation, alpha-synuclein adopts a cross-beta sheet structure characteristic of amyloid fibrils.<ref name="Zigmond_2015">Template:Cite book</ref>
The human alpha-synuclein protein consists of 140 amino acids.<ref name="Ueda_1993">Template:Cite journal</ref><ref name="Xia_2001">Template:Cite journal</ref><ref>Template:Cite journal</ref> A fragment of alpha-synuclein, known as the non-amyloid beta component (NAC) of Alzheimer's disease amyloid, was initially isolated from an amyloid-rich brain fraction and shown to derive from a precursor protein named NACP.<ref name="Ueda_1993" /> NACP was subsequently identified as the human homologue of synuclein from the electric ray genus Torpedo, leading to its renaming as human alpha-synuclein.<ref name="Jakes_1994">Template:Cite journal</ref>
Tissue expressionEdit
Alpha-synuclein is a synuclein protein primarily found in neural tissue, making up as much as one percent of all proteins in the cytosol of brain cells.<ref name="Iwai_1995">Template:Cite journal</ref> It is expressed highly in neurons within the frontal cortex, hippocampus, striatum, and olfactory bulb,<ref name="Iwai_1995" /> but can also be found in the non-neuronal glial cells.<ref>Template:Cite journal</ref> In melanocytes, SNCA protein expression may be regulated by microphthalmia-associated transcription factor (MITF).<ref name="Hoek_2008">Template:Cite journal</ref>
It has been established that alpha-synuclein is extensively localized in the nucleus of mammalian brain neurons, suggesting a role of alpha-synuclein in the nucleus.<ref name="Yu_2007">Template:Cite journal</ref> Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms,<ref name="McLean_2000">Template:Cite journal</ref> with roughly 15% of synuclein being membrane-bound at any moment in neurons.<ref name="Lee_2002">Template:Cite journal</ref>
It has also been shown that alpha-synuclein is localized in neuronal mitochondria.<ref name="pmid 18817762">Template:Cite journal</ref><ref name="pmid 19429081">Template:Cite journal</ref> Alpha-synuclein is highly expressed in the mitochondria in olfactory bulb, hippocampus, striatum and thalamus, where the cytosolic alpha-synuclein is also rich. However, the cerebral cortex and cerebellum are two exceptions, which contain rich cytosolic alpha-synuclein but very low levels of mitochondrial alpha-synuclein. It has been shown that alpha-synuclein is localized in the inner membrane of mitochondria, and that the inhibitory effect of alpha-synuclein on complex I activity of the mitochondrial respiratory chain is dose-dependent. Thus, it is suggested that alpha-synuclein in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.<ref name="pmid 19429081"/>
At least three isoforms of synuclein are produced through alternative splicing.<ref name="Beyer_2006">Template:Cite journal</ref> The majority form of the protein, and the one most investigated, is the full-length protein of 140 amino acids. Other isoforms are alpha-synuclein-126, which lacks residues 41-54 due to loss of exon 3; and alpha-synuclein-112,<ref name="pmid 7802671">Template:Cite journal</ref> which lacks residues 103-130 due to loss of exon 5.<ref name="Beyer_2006" />
In the enteric nervous system (ENS)Edit
First characterisations of aSyn aggregates in the ENS of PD patients has been performed on autopsied specimens in the late 1980s.<ref name="Schaeffer_2020">Template:Cite journal</ref> It is yet unknown if the microbiome changes associated with PD are consequential to the illness process or main pathophysiology, or both.<ref>Template:Cite journal</ref>
Individuals diagnosed with various synucleinopathies often display constipation and other GI dysfunctions years prior to the onset of movement dysfunction.<ref name="Sampson_2020">Template:Cite journal</ref>
Alpha synuclein potentially connects the gut-brain axis in Parkinson's disease patients. Common inherited Parkinson disease is associated with mutations in the alpha-synuclein (SNCA) gene. In the process of seeded nucleation, alpha-synuclein acquires a cross-sheet structure similar to other amyloids.<ref name="Schaeffer_2020" />
The Enterobacteriaceae, which are quite common in the human gut, can create curli, which are functional amyloid proteins. The unfolded amyloid CsgA, which is secreted by bacteria and later aggregates extracellularly to create biofilms, mediates adherence to epithelial cells, and aids in bacteriophage defense, forms the curli fibers. Oral injection of curli-producing bacteria can also boost formation and aggregation of the amyloid protein Syn in old rats and nematodes. Host inflammation responses in the intestinal tract and periphery are modulated by curli exposure. Studies in biochemistry show that endogenous, bacterial chaperones of curli are capable of briefly interacting with Syn and controlling its aggregation.<ref name="Sampson_2020" />
The clinical and pathological findings support the hypothesis that aSyn disease in PD occurs via a gut-brain pathway. For early diagnosis and early management in the phase of creation and propagation of aSyn, it is therefore of utmost importance to identify pathogenic aSyn in the digestive system, for example, by gastrointestinal tract (GIT) biopsies.<ref name="Schaeffer_2020" />
According to a growing body of research, intestinal dysbiosis may be a major factor in the development of Parkinson's disease by encouraging intestinal permeability, gastrointestinal inflammation, and the aggregation and spread of asyn.<ref name="Schaeffer_2020" />
Not just the CNS but other peripheral tissues, such as the GIT, have physiological aSyn expression as well as its phosphorylated variants.<ref>Template:Cite journal</ref> As suggested by Borghammer and Van Den Berge (2019), one approach is to recognise the possibility of PD subtypes with various aSyn propagation methods, including either a peripheral nervous system (PNS)-first or a CNS-first route.<ref>Template:Cite journal</ref>
While the GI tract has been linked to other neurological disorders such autism spectrum disorder, depression, anxiety, and Alzheimer's disease, protein aggregation and/or inflammation in the gut represent a new topic of investigation in synucleinopathies.<ref name="Sampson_2020" />
StructureEdit
Alpha-synuclein in solution is considered to be an intrinsically disordered protein, i.e. it lacks a single stable 3D structure.<ref name="van_Rooijen_2009">Template:Cite journal</ref><ref>Template:Cite journal</ref> As of 2014, an increasing number of reports suggest, however, the presence of partial structures or mostly structured oligomeric states in the solution structure of alpha-synuclein even in the absence of lipids. This trend is also supported by a large number of single molecule (optical tweezers) measurements on single copies of monomeric alpha-synuclein as well as covalently enforced dimers or tetramers of alpha-synuclein.<ref name="Neupane_2014">Template:Cite journal</ref>
Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.<ref name="George_1995">Template:Cite journal</ref> It has been shown that alpha-synuclein significantly interacts with tubulin,<ref name="Alim_2002">Template:Cite journal</ref> and that alpha-synuclein may have activity as a potential microtubule-associated protein, like tau.<ref name="Alim_2004">Template:Cite journal</ref> Evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of SNARE complexes.<ref name="Bonini_2005">Template:Cite journal</ref><ref name="Chandra_2005">Template:Cite journal</ref> In particular, it simultaneously binds to phospholipids of the plasma membrane via its N-terminus domain and to synaptobrevin-2 via its C-terminus domain, with increased importance during synaptic activity.<ref name="Burre_2010">Template:Cite journal</ref> Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal Golgi apparatus and vesicle trafficking.<ref name="Cooper_2006">Template:Cite journal</ref>
Apparently, alpha-synuclein is essential for normal development of the cognitive functions. Knock-out mice with the targeted inactivation of the expression of alpha-synuclein show impaired spatial learning and working memory.<ref name="Kokhan_2012">Template:Cite journal</ref>
Interaction with lipid membranesEdit
Experimental evidence has been collected on the interaction of alpha-synuclein with membrane and its involvement with membrane composition and turnover. Yeast genome screening has found that several genes that deal with lipid metabolism and mitochondrial fusion play a role in alpha-synuclein toxicity.<ref>Template:Cite journal</ref><ref name="Willingham_2003">Template:Cite journal</ref> Conversely, alpha-synuclein expression levels can affect the viscosity and the relative amount of fatty acids in the lipid bilayer.<ref name="Uversky_2007">Template:Cite journal</ref>
Alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids.<ref name="Uversky_2007" /> Alpha-synuclein forms an extended helical structure on small unilamellar vesicles.<ref name="Jao_2008">Template:Cite journal</ref> A preferential binding to small vesicles has been found.<ref name="Zhu_2003">Template:Cite journal</ref> The binding of alpha-synuclein to lipid membranes has complex effects on the latter, altering the bilayer structure and leading to the formation of small vesicles.<ref name="Madine_2006">Template:Cite journal</ref> Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles.<ref name="Varkey_2010">Template:Cite journal</ref> Using cryo-EM it was shown that these are micellar tubes of ~5-6 nm diameter.<ref name="Mizuno_2012">Template:Cite journal</ref> Alpha-synuclein has also been shown to form lipid disc-like particles similar to apolipoproteins.<ref name="Varkey_2013">Template:Cite journal</ref> EPR studies have shown that the structure of alpha synuclein is dependent on the binding surface.<ref name="Varkey J 2017">Template:Cite journal</ref> The protein adopts a broken-helical conformation on lipoprotein particles while it forms an extended helical structure on lipid vesicles and membrane tubes.<ref name="Varkey J 2017"/> Studies have also suggested a possible antioxidant activity of alpha-synuclein in the membrane.<ref name="Zhu_2006">Template:Cite journal</ref>
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Membrane interaction of alpha-synuclein modulates or affects its rate of aggregation.<ref name="Rawat A 2018">Template:Cite journal</ref> The membrane-mediated modulation of aggregation is very similar to that observed for other amyloid proteins such as IAPP and abeta.<ref name="Rawat A 2018"/> Aggregated states of alpha-synuclein permeate the membrane of lipid vesicles.<ref>Template:Cite journal</ref> They are formed upon interaction with peroxidation-prone polyunsaturated fatty acids (PUFA) but not with monounsaturated fatty acids<ref>Template:Cite journal</ref> and the binding of lipid autoxidation-promoting transition metals such as iron or copper provokes oligomerization of alpha-synuclein.<ref>Template:Cite journal</ref> The aggregated alpha-synuclein has a specific activity for peroxidized lipids and induces lipid autoxidation in PUFA-rich membranes of both neurons and astrocytes, decreasing resistance to apoptosis.<ref>Template:Cite journal</ref> Lipid autoxidation is inhibited if the cells are pre-incubated with isotope-reinforced PUFAs (D-PUFA).<ref>Template:Cite journal</ref>
FunctionEdit
Although the function of alpha-synuclein is not well understood, studies suggest that it plays a role in restricting the mobility of synaptic vesicles, consequently attenuating synaptic vesicle recycling and neurotransmitter release.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Sun_2019">Template:Cite journal</ref> An alternate view is that alpha-synuclein binds to VAMP2 (a synaptobrevin) and stabilizes SNARE complexes;<ref name="Burre_2010" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Diao_2013">Template:Cite journal</ref> though recent studies indicate that alpha-synuclein–VAMP2 binding is critical for alpha-synuclein-mediated attenuation of synaptic vesicle recycling, connecting the two seemingly divergent views.<ref name="Sun_2019" /> It may also help regulate the release of dopamine, a type of neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements.<ref name="ghrsnca" />
Alpha-synuclein modulates DNA repair processes, including repair of double-strand breaks (DSBs).<ref name="Schaser_2019">Template:Cite journal</ref> DNA damage response markers co-localize with alpha-synuclein to form discrete foci in human cells and mouse brain. Depletion of alpha-synuclein in human cells causes increased introduction of DNA DSBs after exposure to bleomycin and reduced ability to repair these DSBs. In addition, alpha-synuclein knockout mice display a higher level of DSBs, and this problem can be alleviated by transgenic reintroduction of human alpha-synuclein. Alpha-synuclein promotes the DSB repair pathway referred to as non-homologous end joining.<ref name="Schaser_2019" /> The DNA repair function of alpha-synuclein appears to be compromised in Lewy body inclusion bearing neurons, and this may trigger cell death.
Proneurogenic function of alpha-synucleinEdit
In some neurodegenerative diseases, alpha-synuclein produces insoluble inclusion bodies. These diseases, known as synucleinopathies, are connected with either higher levels of normal alpha-synuclein or its mutant variants.<ref>Template:Cite journal</ref> The normal physiological role of Snca, however, has not yet been thoroughly explained. In fact, physiological Snca has been demonstrated to have a neuroprotective impact by inhibiting apoptosis induced by several types of apoptotic stimuli, or by regulating the expression of proteins involved in apoptotic pathways. Recently it has been demonstrated that up-regulation of alpha-synuclein in the dentate gyrus (a neurogenic niche where new neurons are generated throughout life) activates stem cells, in a model of premature neural aging. This model shows reduced expression of alpha-synuclein and reduced proliferation of stem cells, as is physiologically observed during aging. Exogenous alpha-synuclein in the dentate gyrus is able to rescue this defect. Moreover, alpha-synuclein also boosts the proliferation of dentate gyrus progenitor neural cells in wild-type young mice. Thus, alpha-synuclein represents an effector for neural stem and progenitor cell activation.<ref>Template:Cite journal</ref> Similarly, alpha-synuclein has been found to be required to maintain stem cells of the SVZ (subventricular zone, i.e., another neurogenic niche) in a cycling state.<ref>Template:Cite journal</ref>
SequenceEdit
Alpha-synuclein primary structure is usually divided in three distinct domains:
- Residues 1-60: An amphipathic N-terminal region dominated by four 11-residue repeats including the consensus sequence KTKEGV. This sequence has a structural alpha helix propensity similar to apolipoproteins-binding domains.<ref>Template:Cite journal</ref> It is a highly conserved terminal that interacts with acidic lipid membranes, and all the discovered point mutations of the SNCA gene are located within this terminal.<ref>Template:Cite journal</ref>
- Residues 61-95: A central hydrophobic region which includes the non-amyloid-β component (NAC) region, involved in protein aggregation.<ref name="Ueda_1993" /> This domain is unique to alpha-synuclein among the synuclein family.<ref>Template:Cite journal</ref>
- Residues 96-140: a highly acidic and proline-rich region which has no distinct structural propensity. This domain plays an important role in the function, solubility and interaction of alpha-synuclein with other proteins.<ref>Template:Cite journal</ref><ref name="Burre_2010" />
Autoproteolytic activityEdit
The use of high-resolution ion-mobility mass spectrometry (IMS-MS) on HPLC-purified alpha-synuclein in vitro has shown alpha-synuclein to be autoproteolytic (self-proteolytic), generating a variety of small molecular weight fragments upon incubation.<ref name="Vlad_2011">Template:Cite journal</ref> The 14.46 kDa protein was found to generate numerous smaller fragments, including 12.16 kDa (amino acids 14–133) and 10.44 kDa (40–140) fragments formed through C- and N-terminal truncation and a 7.27 kDa C-terminal fragment (72–140). The 7.27 kDa fragment, which contains the majority of the NAC region, aggregated considerably faster than full-length alpha-synuclein. It is possible that these autoproteolytic products play a role as intermediates or cofactors in the aggregation of alpha-synuclein in vivo.
Clinical significanceEdit
Alpha synuclein, having no single, well-defined tertiary structure, is an intrinsically disordered protein,<ref>Template:Cite journal</ref><ref name="Half a century of amyloids: past, p">Template:Cite journal</ref> with a pI value of 4.7,<ref>Template:Cite journal</ref> which, under certain pathological conditions, can misfold in a way that exposes its core hydrophobic residues to the intracellular milieu, thus providing the opportunity for hydrophobic interactions to occur with a similar, equally exposed protein.<ref name="Half a century of amyloids: past, p"/> This could lead to self assembly and subsequent aggregation into large, insoluble fibrils known as amyloids.<ref name="Half a century of amyloids: past, p"/> The conversion of soluble alpha synuclein into highly ordered, cross-β sheet, fibrillar structures does not, as previously thought, follow a two-step mechanism, rather, occurs through a series of transient, soluble oligomeric intermediates.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In 2011, two groups published their findings that unmutated α-synuclein forms a stably folded tetramer that resists aggregation, asserting that this folded tetramer represented the relevant in vivo structure in cells,<ref name="Bartels_2011">Template:Cite journal</ref><ref>Template:Cite journal</ref> thereby relieving alpha synuclein of its disordered status. Proponents of the tetramer hypothesis argued that in vivo cross-linking in bacteria, primary neurons and human erythroleukemia cells confirmed the presence of labile, tetrameric species.<ref name="Dettmer_2013">Template:Cite journal</ref><ref name="Westphal_2013">Template:Cite journal</ref><ref name="Trexler_2012">Template:Cite journal</ref> However, despite numerous in-cell NMR reports demonstrating that alpha synuclein is indeed monomeric and disordered in intact E. coli cells,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Fauvet_2012" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> it is still a matter of debate in the field despite an ever growing mountain of conflicting reports.<ref name="Fauvet_2012">Template:Cite journal</ref><ref name="Burre_2013">Template:Cite journal</ref><ref name="Theillet_2016">Template:Cite journal</ref> Nevertheless, alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.<ref name="Spillantini_1997">Template:Cite journal</ref><ref name="Mezey_1998">Template:Cite journal</ref> These disorders are known as synucleinopathies. In vitro models of synucleinopathies revealed that aggregation of alpha-synuclein may lead to various cellular disorders including microtubule impairment, synaptic and mitochondrial dysfunctions, oxidative stress as well as dysregulation of Calcium signaling, proteasomal and lysosomal pathway.<ref>Template:Cite journal</ref> Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein;<ref name="pmid 10528110">Template:Cite journal</ref> however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies.<ref name="Arima_2000">Template:Cite journal</ref> Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.<ref name="Yokota_2002">Template:Cite journal</ref>
The aggregation mechanism of alpha-synuclein is uncertain. There is evidence of a structured intermediate rich in beta structure that can be the precursor of aggregation and, ultimately, Lewy bodies.<ref name="Kim_2007">Template:Cite journal</ref> A single molecule study in 2008 suggests alpha-synuclein exists as a mix of unstructured, alpha-helix, and beta-sheet-rich conformers in equilibrium. Mutations or buffer conditions known to improve aggregation strongly increase the population of the beta conformer, thus suggesting this could be a conformation related to pathogenic aggregation.<ref name="Sandal_2008">Template:Cite journal</ref> One theory is that the majority of alpha-synuclein aggregates are located in the presynapse as smaller deposits which causes synaptic dysfunction.<ref>Template:Cite journal</ref> Among the strategies for treating synucleinopathies are compounds that inhibit aggregation of alpha-synuclein. It has been shown that the small molecule cuminaldehyde inhibits fibrillation of alpha-synuclein.<ref>Template:Cite journal</ref> The Epstein-Barr virus has been implicated in these disorders.<ref>Template:Cite journal</ref>
In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for alpha-synuclein. Five point mutations have been identified thus far: A53T,<ref name="Polymeropoulos_1997">Template:Cite journal</ref> A30P,<ref name="Kruger_1998">Template:Cite journal</ref> E46K,<ref name="Zarranz_2004">Template:Cite journal</ref> H50Q,<ref name="AppelCresswell_2013">Template:Cite journal</ref> and G51D;<ref name="Lesage_2013">Template:Cite journal</ref> however, in total, nineteen mutations in the SNCA gene have been associated with parkinsonism: A18T, A29S, A53E, A53V, E57A, V15A, T72M, L8I, V15D, M127I, P117S, M5T, G93A, E83Q, and A30G.<ref>Template:Cite journal</ref>
It has been reported that some mutations influence the initiation and amplification steps of the aggregation process.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Genomic duplication and triplication of the gene appear to be a rare cause of Parkinson's disease in other lineages, although more common than point mutations.<ref name="Singleton_2003">Template:Cite journal</ref><ref name="ChartierHarlin_2004">Template:Cite journal</ref> Hence certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to Parkinson's disease. Over-expression of human wild-type or A53T-mutant alpha-synuclein in primates drives deposition of alpha-synuclein in the ventral midbrain, degeneration of the dopaminergic system and impaired motor performance.<ref>Template:Cite journal</ref> Although the accumulation and aggregation of alpha-synuclein in most Parkinson's disease patients primarily result from posttranscriptional mechanisms, targeting its production remains a potential therapeutic approach.<ref>Template:Cite journal</ref> Research indicates that microRNA-7 and the naturally occurring small molecule quercetin can reduce alpha-synuclein levels under experimental conditions.<ref>Template:Cite journal</ref>
Certain sections of the alpha-synuclein protein may play a role in the tauopathies.<ref>Template:Cite journal</ref><ref name="Takeda_2000">Template:Cite journal</ref><ref>Template:Cite journal</ref>
A prion form of the protein alpha-synuclein may be a causal agent for the disease multiple system atrophy.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>
Self-replicating "prion-like" amyloid assemblies of alpha-synuclein have been described that are invisible to the amyloid dye Thioflavin T and that can acutely spread in neurons in vitro and in vivo.<ref>Template:Cite journal</ref> Template:More citations needed section
Antibodies against alpha-synuclein have replaced antibodies against ubiquitin as the gold standard for immunostaining of Lewy bodies.<ref>Template:Cite journal</ref> The central panel in the figure to the right shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons.
Protein-protein interactionsEdit
Alpha-synuclein has been shown to interact with
- Dopamine transporter,<ref name="Wersinger_2003">Template:Cite journal</ref><ref name="Lee_2001">Template:Cite journal</ref>
- Parkin (ligase),<ref name="Choi_2001">Template:Cite journal</ref><ref name="Kawahara_2008">Template:Cite journal</ref>
- Phospholipase D1,<ref name="Ahn_2002">Template:Cite journal</ref>
- SNCAIP,<ref name="Neystat_2002">Template:Cite journal</ref><ref name="Reed_1991">Template:Cite journal</ref><ref name="Kawamata_2001">Template:Cite journal</ref><ref name="Engelender_1999">Template:Cite journal</ref>
- Tau protein.<ref>Template:Cite journal</ref><ref name="Jensen_1999">Template:Cite journal</ref><ref>Template:Cite journal</ref>
- Beta amyloid<ref name="Ono_2012">Template:Cite journal</ref>
See alsoEdit
- Synuclein
- Contursi Terme - the village in Italy where a mutation in the α-synuclein gene led to a family history of Parkinson's disease
- Anti-α-synuclein drug
ReferencesEdit
Further readingEdit
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