View source for Alpha-synuclein

{{Short description|Protein found in humans}}
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{{Infobox gene}}
'''Alpha-synuclein''' ('''aSyn''') is a [[protein]] that in humans is encoded by the ''SNCA'' [[gene]].<ref name="ghrsnca">{{cite web | work = Genetics Home Reference | title = SNCA | date = 12 Nov 2013 | url = https://medlineplus.gov/genetics/gene/snca/ | publisher = U.S. National Library of Medicine | access-date = 14 Nov 2013 }}</ref> It is a neuronal protein involved in the regulation of [[synaptic vesicle trafficking]] and the release of [[neurotransmitter]]s.<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 terminal]]s of [[presynaptic neuron]]s.<ref name="ghrsnca" /> There, it interacts with [[phospholipid]]s<ref>{{cite journal | vauthors = Chandra S, Chen X, Rizo J, Jahn R, Südhof TC | title = A broken alpha -helix in folded alpha -Synuclein | journal = The Journal of Biological Chemistry | volume = 278 | issue = 17 | pages = 15313–15318 | date = April 2003 | pmid = 12586824 | doi = 10.1074/jbc.M213128200 | s2cid = 27116894 | doi-access = free }}</ref> and other proteins.<ref name="ghrsnca" /><ref name="Sun_2019" /><ref>{{cite journal | vauthors = Atias M, Tevet Y, Sun J, Stavsky A, Tal S, Kahn J, Roy S, Gitler D | title = Synapsins regulate α-synuclein functions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 23 | pages = 11116–11118 | date = June 2019 | pmid = 31110014 | pmc = 6561288 | doi = 10.1073/pnas.1903054116 | bibcode = 2019PNAS..11611116A | doi-access = free }}</ref> Presynaptic terminals release neurotransmitters from specialized compartments called [[synaptic vesicle]]s, 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 [[inclusion bodies|inclusions]] known as [[Lewy body|Lewy bodies]].<ref>{{cite journal | vauthors = Spillantini MG, Schmidt ML, Lee VM, Trojanowkski JQ, Jakes R, Goedert M | title = α-Synuclein in Lewy bodies | journal = Nature | volume = 388 | issue = 6645 | pages = 839–840 | date = 28 August 1997 | pmid = 9278044 | doi = 10.1038/42166 | bibcode = 1997Natur.388..839G | s2cid = 4419837 | doi-access = free }}</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">{{cite book | vauthors = Zigmond MJ, Coyle JT, Rowland JP | title = Neurobiology of brain disorders: biological basis of neurological and psychiatric disorders | location = London | publisher = Academic Press | date = 2015 | isbn = 978-0-12-398280-3 | oclc = 896232309 }}</ref>

The human alpha-synuclein protein consists of 140 amino acids.<ref name="Ueda_1993">{{cite journal | vauthors = Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T | title = Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 11282–11286 | date = December 1993 | pmid = 8248242 | pmc = 47966 | doi = 10.1073/pnas.90.23.11282 | doi-access = free | bibcode = 1993PNAS...9011282U }}</ref><ref name="Xia_2001">{{cite journal | vauthors = Xia Y, Saitoh T, Uéda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E | title = Characterization of the human alpha-synuclein gene: Genomic structure, transcription start site, promoter region and polymorphisms | journal = Journal of Alzheimer's Disease | volume = 3 | issue = 5 | pages = 485–494 | date = October 2001 | pmid = 12214035 | doi = 10.3233/JAD-2001-3508 | url = http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | access-date = 2009-02-19 | archive-url = http://arquivo.pt/wayback/20160514170300/http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | archive-date = 2016-05-14 }}</ref><ref>{{cite journal | vauthors = Xia Y, Saitoh T, Uéda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E | title = Characterization of the human alpha-synuclein gene: Genomic structure, transcription start site, promoter region and polymorphisms: Erratum p489 Fig 3 | journal = J. Alzheimer's Dis. | volume = 4 | issue = 4 | page = 337 | year = 2002 | url = http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | archive-url = http://arquivo.pt/wayback/20160514170300/http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | archive-date = 2016-05-14 | access-date = 2009-02-19 }}</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 (genus)|Torpedo]]'', leading to its renaming as human alpha-synuclein.<ref name="Jakes_1994">{{cite journal | vauthors = Jakes R, Spillantini MG, Goedert M | title = Identification of two distinct synucleins from human brain | journal = FEBS Letters | volume = 345 | issue = 1 | pages = 27–32 | date = May 1994 | pmid = 8194594 | doi = 10.1016/0014-5793(94)00395-5 | s2cid = 36840279 | doi-access = free | bibcode = 1994FEBSL.345...27J }}</ref>

== Tissue expression ==

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 cell]]s.<ref name="Iwai_1995">{{cite journal | vauthors = Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T | title = The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system | journal = Neuron | volume = 14 | issue = 2 | pages = 467–475 | date = February 1995 | pmid = 7857654 | doi = 10.1016/0896-6273(95)90302-X | s2cid = 17941420 | doi-access = free }}</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>{{cite journal | vauthors = Filippini A, Gennarelli M, Russo I | title = α-Synuclein and Glia in Parkinson's Disease: A Beneficial or a Detrimental Duet for the Endo-Lysosomal System? | journal = Cellular and Molecular Neurobiology | volume = 39 | issue = 2 | pages = 161–168 | date = March 2019 | pmid = 30637614 | pmc = 11469870 | doi = 10.1007/s10571-019-00649-9 | s2cid = 58006790 }}</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">{{cite journal | vauthors = Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Uéda K, Chan P | title = Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody | journal = Neuroscience | volume = 145 | issue = 2 | pages = 539–555 | date = March 2007 | pmid = 17275196 | doi = 10.1016/j.neuroscience.2006.12.028 | s2cid = 37294944 }}</ref> Synuclein is however found predominantly in the [[presynaptic]] termini, in both free or membrane-bound forms,<ref name="McLean_2000">{{cite journal | vauthors = McLean PJ, Kawamata H, Ribich S, Hyman BT | title = Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson's disease-linked mutations | journal = The Journal of Biological Chemistry | volume = 275 | issue = 12 | pages = 8812–8816 | date = March 2000 | pmid = 10722726 | doi = 10.1074/jbc.275.12.8812 | doi-access = free }}</ref> with roughly 15% of synuclein being membrane-bound at any moment in neurons.<ref name="Lee_2002">{{cite journal | vauthors = Lee HJ, Choi C, Lee SJ | title = Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form | journal = The Journal of Biological Chemistry | volume = 277 | issue = 1 | pages = 671–678 | date = January 2002 | pmid = 11679584 | doi = 10.1074/jbc.M107045200 | s2cid = 10438997 | doi-access = free }}</ref>

It has also been shown that alpha-synuclein is localized in neuronal [[mitochondria]].<ref name="pmid 18817762">{{cite journal | vauthors = Zhang L, Zhang C, Zhu Y, Cai Q, Chan P, Uéda K, Yu S, Yang H | title = Semi-quantitative analysis of alpha-synuclein in subcellular pools of rat brain neurons: an immunogold electron microscopic study using a C-terminal specific monoclonal antibody | journal = Brain Research | volume = 1244 | pages = 40–52 | date = December 2008 | pmid = 18817762 | doi = 10.1016/j.brainres.2008.08.067 | s2cid = 1737088 }}</ref><ref name="pmid 19429081">{{cite journal | vauthors = Liu G, Zhang C, Yin J, Li X, Cheng F, Li Y, Yang H, Uéda K, Chan P, Yu S | title = alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity | journal = Neuroscience Letters | volume = 454 | issue = 3 | pages = 187–192 | date = May 2009 | pmid = 19429081 | doi = 10.1016/j.neulet.2009.02.056 | s2cid = 45120745 }}</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 [[Respiratory complex I|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">{{cite journal | vauthors = Beyer K | title = Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers | journal = Acta Neuropathologica | volume = 112 | issue = 3 | pages = 237–251 | date = September 2006 | pmid = 16845533 | doi = 10.1007/s00401-006-0104-6 | s2cid = 1367846 }}</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">{{cite journal | vauthors = Uéda K, Saitoh T, Mori H | title = Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer's disease amyloid | journal = Biochemical and Biophysical Research Communications | volume = 205 | issue = 2 | pages = 1366–1372 | date = December 1994 | pmid = 7802671 | doi = 10.1006/bbrc.1994.2816 }}</ref> which lacks residues 103-130 due to loss of exon 5.<ref name="Beyer_2006" />

=== In the enteric nervous system (ENS) ===
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">{{cite journal | vauthors = Schaeffer E, Kluge A, Böttner M, Zunke F, Cossais F, Berg D, Arnold P | title = Alpha Synuclein Connects the Gut-Brain Axis in Parkinson's Disease Patients - A View on Clinical Aspects, Cellular Pathology and Analytical Methodology | journal = Frontiers in Cell and Developmental Biology | volume = 8 | article-number = 573696 | date = 2020 | pmid = 33015066 | pmc = 7509446 | doi = 10.3389/fcell.2020.573696 | doi-access = free }}</ref> It is yet unknown if the microbiome changes associated with PD are consequential to the illness process or main pathophysiology, or both.<ref>{{cite journal | vauthors = Anis E, Xie A, Brundin L, Brundin P | title = Digesting recent findings: gut alpha-synuclein, microbiome changes in Parkinson's disease | journal = Trends in Endocrinology and Metabolism  | volume = 33 | issue = 2 | pages = 147–157 | date = February 2022 | pmid = 34949514 | doi = 10.1016/j.tem.2021.11.005 | language = English | s2cid = 245351514 }}</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">{{cite journal | vauthors = Sampson TR, Challis C, Jain N, Moiseyenko A, Ladinsky MS, Shastri GG, Thron T, Needham BD, Horvath I, Debelius JW, Janssen S, Knight R, Wittung-Stafshede P, Gradinaru V, Chapman M, Mazmanian SK | veditors = Chiu IM, Garrett WS, Desjardins M | title = A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice | journal = eLife | volume = 9 | article-number = e53111 | date = February 2020 | pmid = 32043464 | pmc = 7012599 | doi = 10.7554/eLife.53111 | doi-access = free }}</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 [[nematode]]s. 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>{{cite journal | vauthors = Barrenschee M, Zorenkov D, Böttner M, Lange C, Cossais F, Scharf AB, Deuschl G, Schneider SA, Ellrichmann M, Fritscher-Ravens A, Wedel T | title = Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson's disease | journal = Acta Neuropathologica Communications | volume = 5 | issue = 1 | article-number = 1 | date = January 2017 | pmid = 28057070 | pmc = 5217296 | doi = 10.1186/s40478-016-0408-2 | doi-access = free }}</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>{{cite journal | vauthors = Borghammer P, Van Den Berge N | title = Brain-First versus Gut-First Parkinson's Disease: A Hypothesis | journal = Journal of Parkinson's Disease | volume = 9 | issue = s2 | pages = S281–S295 | date = 2019-10-30 | pmid = 31498132 | pmc = 6839496 | doi = 10.3233/jpd-191721 }}</ref>

While the GI tract has been linked to other neurological disorders such [[Autism spectrum|autism spectrum disorder]], [[Depression (mood)|depression]], [[anxiety]], and [[Alzheimer's disease]], protein aggregation and/or inflammation in the gut represent a new topic of investigation in [[Synucleinopathy|synucleinopathies]].<ref name="Sampson_2020" />

== Structure ==

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">{{cite journal | vauthors = van Rooijen BD, van Leijenhorst-Groener KA, Claessens MM, Subramaniam V | title = Tryptophan fluorescence reveals structural features of alpha-synuclein oligomers | journal = Journal of Molecular Biology | volume = 394 | issue = 5 | pages = 826–833 | date = December 2009 | pmid = 19837084 | doi = 10.1016/j.jmb.2009.10.021 | s2cid = 36085937 | url = https://ris.utwente.nl/ws/files/6758594/Rooijen09tryptophan.pdf }}</ref><ref>{{cite journal | vauthors = Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT | title = NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded | journal = Biochemistry | volume = 35 | issue = 43 | pages = 13709–13715 | date = October 1996 | pmid = 8901511 | doi = 10.1021/bi961799n }}</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 [[protein dimer|dimer]]s or [[tetramer]]s of alpha-synuclein.<ref name="Neupane_2014">{{cite journal | vauthors = Neupane K, Solanki A, Sosova I, Belov M, Woodside MT | title = Diverse metastable structures formed by small oligomers of α-synuclein probed by force spectroscopy | journal = PLOS ONE | volume = 9 | issue = 1 | article-number = e86495 | date = January 2014 | pmid = 24475132 | pmc = 3901707 | doi = 10.1371/journal.pone.0086495 | doi-access = free | bibcode = 2014PLoSO...986495N }}</ref>

Alpha-synuclein is specifically [[Regulation of gene expression|upregulated]] in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.<ref name="George_1995">{{cite journal | vauthors = George JM, Jin H, Woods WS, Clayton DF | title = Characterization of a novel protein regulated during the critical period for song learning in the zebra finch | journal = Neuron | volume = 15 | issue = 2 | pages = 361–372 | date = August 1995 | pmid = 7646890 | doi = 10.1016/0896-6273(95)90040-3 | s2cid = 11421888 | doi-access = free }}</ref> It has been shown that alpha-synuclein significantly interacts with [[tubulin]],<ref name="Alim_2002">{{cite journal | vauthors = Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T, Hisanaga S, Ueda K | title = Tubulin seeds alpha-synuclein fibril formation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 3 | pages = 2112–2117 | date = January 2002 | pmid = 11698390 | doi = 10.1074/jbc.M102981200 | s2cid = 84374030 | doi-access = free }}</ref> and that alpha-synuclein may have activity as a potential [[microtubule-associated protein]], like [[Tau protein|tau]].<ref name="Alim_2004">{{cite journal | vauthors = Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada A, Saito T, Kaji H, Yoshii M, Hisanaga S, Uéda K | title = Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein | journal = Journal of Alzheimer's Disease | volume = 6 | issue = 4 | pages = 435–42; discussion 443–9 | date = August 2004 | pmid = 15345814 | doi = 10.3233/JAD-2004-6412 }}</ref> Evidence suggests that alpha-synuclein functions as a [[molecular chaperone]] in the formation of [[SNARE (protein)|SNARE]] complexes.<ref name="Bonini_2005">{{cite journal | vauthors = Bonini NM, Giasson BI | title = Snaring the function of alpha-synuclein | journal = Cell | volume = 123 | issue = 3 | pages = 359–361 | date = November 2005 | pmid = 16269324 | doi = 10.1016/j.cell.2005.10.017 | s2cid = 18772904 | doi-access = free }}</ref><ref name="Chandra_2005">{{cite journal | vauthors = Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC | title = Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration | journal = Cell | volume = 123 | issue = 3 | pages = 383–396 | date = November 2005 | pmid = 16269331 | doi = 10.1016/j.cell.2005.09.028 | s2cid = 18173864 | doi-access = free }}</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">{{cite journal | vauthors = Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC | title = Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro | journal = Science | location = New York, N.Y. | volume = 329 | issue = 5999 | pages = 1663–1667 | date = September 2010 | pmid = 20798282 | pmc = 3235365 | doi = 10.1126/science.1195227 | bibcode = 2010Sci...329.1663B }}</ref> Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal [[Golgi apparatus]] and [[Vesicle (biology)|vesicle]] trafficking.<ref name="Cooper_2006">{{cite journal | vauthors = Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S | title = Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models | journal = Science | location = New York, N.Y. | volume = 313 | issue = 5785 | pages = 324–328 | date = July 2006 | pmid = 16794039 | pmc = 1983366 | doi = 10.1126/science.1129462 | bibcode = 2006Sci...313..324C }}</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">{{cite journal | vauthors = Kokhan VS, Afanasyeva MA, Van'kin GI | title = α-Synuclein knockout mice have cognitive impairments | journal = Behavioural Brain Research | volume = 231 | issue = 1 | pages = 226–230 | date = May 2012 | pmid = 22469626 | doi = 10.1016/j.bbr.2012.03.026 | s2cid = 205884600 }}</ref>

=== Interaction with lipid membranes ===

Experimental evidence has been collected on the interaction of alpha-synuclein with [[cell membrane|membrane]] and its involvement with membrane composition and turnover. [[Saccharomyces cerevisiae|Yeast]] genome screening has found that several genes that deal with lipid metabolism and mitochondrial fusion play a role in alpha-synuclein toxicity.<ref>{{cite journal | vauthors = Tauro M | title = Alpha-Synuclein Toxicity is Caused by Mitochondrial Dysfunction | journal = Electronic Thesis and Dissertation Repository | date = 4 February 2019 | url = https://ir.lib.uwo.ca/etd/6019 }}</ref><ref name="Willingham_2003">{{cite journal | vauthors = Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ | title = Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein | journal = Science | location = New York, N.Y. | volume = 302 | issue = 5651 | pages = 1769–1772 | date = December 2003 | pmid = 14657499 | doi = 10.1126/science.1090389 | s2cid = 43221047 | bibcode = 2003Sci...302.1769W }}</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">{{cite journal | vauthors = Uversky VN | title = Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation | journal = Journal of Neurochemistry | volume = 103 | issue = 1 | pages = 17–37 | date = October 2007 | pmid = 17623039 | doi = 10.1111/j.1471-4159.2007.04764.x | s2cid = 85334400 }}</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">{{cite journal | vauthors = Jao CC, Hegde BG, Chen J, Haworth IS, Langen R | title = Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 50 | pages = 19666–19671 | date = December 2008 | pmid = 19066219 | pmc = 2605001 | doi = 10.1073/pnas.0807826105 | doi-access = free | bibcode = 2008PNAS..10519666J }}</ref> A preferential binding to small vesicles has been found.<ref name="Zhu_2003">{{cite journal | vauthors = Zhu M, Li J, Fink AL | title = The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 40186–40197 | date = October 2003 | pmid = 12885775 | doi = 10.1074/jbc.M305326200 | s2cid = 41555488 | doi-access = free }}</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">{{cite journal | vauthors = Madine J, Doig AJ, Middleton DA | title = A study of the regional effects of alpha-synuclein on the organization and stability of phospholipid bilayers | journal = Biochemistry | volume = 45 | issue = 18 | pages = 5783–5792 | date = May 2006 | pmid = 16669622 | doi = 10.1021/bi052151q }}</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">{{cite journal | vauthors = Varkey J, Isas JM, Mizuno N, Jensen MB, Bhatia VK, Jao CC, Petrlova J, Voss JC, Stamou DG, Steven AC, Langen R | title = Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins | journal = The Journal of Biological Chemistry | volume = 285 | issue = 42 | pages = 32486–32493 | date = October 2010 | pmid = 20693280 | pmc = 2952250 | doi = 10.1074/jbc.M110.139576 | doi-access = free }}</ref> Using [[cryo-EM]] it was shown that these are micellar tubes of ~5-6&nbsp;nm diameter.<ref name="Mizuno_2012">{{cite journal | vauthors = Mizuno N, Varkey J, Kegulian NC, Hegde BG, Cheng N, Langen R, Steven AC | title = Remodeling of lipid vesicles into cylindrical micelles by α-synuclein in an extended α-helical conformation | journal = The Journal of Biological Chemistry | volume = 287 | issue = 35 | pages = 29301–29311 | date = August 2012 | pmid = 22767608 | pmc = 3436199 | doi = 10.1074/jbc.M112.365817 | doi-access = free }}</ref> Alpha-synuclein has also been shown to form lipid disc-like particles similar to [[apolipoproteins]].<ref name="Varkey_2013">{{cite journal | vauthors = Varkey J, Mizuno N, Hegde BG, Cheng N, Steven AC, Langen R | title = α-Synuclein oligomers with broken helical conformation form lipoprotein nanoparticles | journal = The Journal of Biological Chemistry | volume = 288 | issue = 24 | pages = 17620–17630 | date = June 2013 | pmid = 23609437 | pmc = 3682563 | doi = 10.1074/jbc.M113.476697 | doi-access = free }}</ref> EPR studies have shown that the structure of alpha synuclein is dependent on the binding surface.<ref name="Varkey J 2017">{{cite journal | vauthors = Varkey J, Langen R | title = Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR | journal = Journal of Magnetic Resonance | location = San Diego, Calif. | volume = 280 | pages = 127–139 | date = July 2017 | pmid = 28579098 | pmc = 5461824 | doi = 10.1016/j.jmr.2017.02.014 | bibcode = 2017JMagR.280..127V }}</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">{{cite journal | vauthors = Zhu M, Qin ZJ, Hu D, Munishkina LA, Fink AL | title = Alpha-synuclein can function as an antioxidant preventing oxidation of unsaturated lipid in vesicles | journal = Biochemistry | volume = 45 | issue = 26 | pages = 8135–8142 | date = July 2006 | pmid = 16800638 | doi = 10.1021/bi052584t }}</ref> 
[[File:Lewy bodies (alpha synuclein inclusions).svg|right|thumb|Photomicrographs of regions of substantia nigra in a patient showing Lewy bodies and Lewy neurites in various magnifications]]  Membrane interaction of alpha-synuclein modulates or affects its rate of aggregation.<ref name="Rawat A 2018">{{cite journal | vauthors = Rawat A, Langen R, Varkey J | title = Membranes as modulators of amyloid protein misfolding and target of toxicity | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1860 | issue = 9 | pages = 1863–1875 | date = September 2018 | pmid = 29702073 | pmc = 6203680 | doi = 10.1016/j.bbamem.2018.04.011 }}</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>{{cite journal | vauthors = Flagmeier P, De S, Wirthensohn DC, Lee SF, Vincke C, Muyldermans S, Knowles TP, Gandhi S, Dobson CM, Klenerman D | title = Ultrasensitive Measurement of Ca<sup>2+</sup> Influx into Lipid Vesicles Induced by Protein Aggregates | journal = Angewandte Chemie | location = International Ed. in English | volume = 56 | issue = 27 | pages = 7750–7754 | date = June 2017 | pmid = 28474754 | pmc = 5615231 | doi = 10.1002/anie.201700966 }}</ref> They are formed upon interaction with peroxidation-prone [[polyunsaturated fatty acid]]s (PUFA) but not with [[monounsaturated fatty acid]]s<ref>{{cite journal | vauthors = Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ | title = The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease | journal = Neuron | volume = 37 | issue = 4 | pages = 583–595 | date = February 2003 | pmid = 12597857 | doi = 10.1016/s0896-6273(03)00024-2 | s2cid = 1604719 | doi-access = free }}</ref> and the binding of lipid [[autoxidation]]-promoting [[transition metal]]s such as [[iron]] or [[copper]] provokes oligomerization of alpha-synuclein.<ref>{{cite journal | vauthors = Amer DA, Irvine GB, El-Agnaf OM | title = Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders | journal = Experimental Brain Research | volume = 173 | issue = 2 | pages = 223–233 | date = August 2006 | pmid = 16733698 | doi = 10.1007/s00221-006-0539-y | s2cid = 24760126 }}</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>{{cite journal | vauthors = Ruipérez V, Darios F, Davletov B | title = Alpha-synuclein, lipids and Parkinson's disease | journal = Progress in Lipid Research | volume = 49 | issue = 4 | pages = 420–428 | date = October 2010 | pmid = 20580911 | doi = 10.1016/j.plipres.2010.05.004 }}</ref> Lipid autoxidation is inhibited if the cells are pre-incubated with [[Deuterated drug|isotope-reinforced]] PUFAs (D-PUFA).<ref>{{cite journal | vauthors = Angelova PR, Horrocks MH, Klenerman D, Gandhi S, Abramov AY, Shchepinov MS | title = Lipid peroxidation is essential for α-synuclein-induced cell death | journal = Journal of Neurochemistry | volume = 133 | issue = 4 | pages = 582–589 | date = May 2015 | pmid = 25580849 | pmc = 4471127 | doi = 10.1111/jnc.13024 }}</ref>

== Function ==

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>{{cite journal | vauthors = Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P, Quazi AZ, Savalle M, Nemani V, Chaudhry FA, Edwards RH, Stefanis L, Sulzer D | title = Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis | journal = The Journal of Neuroscience| volume = 26 | issue = 46 | pages = 11915–11922 | date = November 2006 | pmid = 17108165 | pmc = 6674868 | doi = 10.1523/JNEUROSCI.3821-06.2006 }}</ref><ref>{{cite journal | vauthors = Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH | title = Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis | journal = Neuron | volume = 65 | issue = 1 | pages = 66–79 | date = January 2010 | pmid = 20152114 | pmc = 3119527 | doi = 10.1016/j.neuron.2009.12.023 }}</ref><ref>{{cite journal | vauthors = Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S | title = A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration | journal = The Journal of Neuroscience| volume = 30 | issue = 24 | pages = 8083–8095 | date = June 2010 | pmid = 20554859 | pmc = 2901533 | doi = 10.1523/JNEUROSCI.1091-10.2010 }}</ref><ref>{{cite journal | vauthors = Scott D, Roy S | title = α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis | journal = The Journal of Neuroscience| volume = 32 | issue = 30 | pages = 10129–10135 | date = July 2012 | pmid = 22836248 | pmc = 3426499 | doi = 10.1523/JNEUROSCI.0535-12.2012 }}</ref><ref>{{cite journal | vauthors = Vargas KJ, Makani S, Davis T, Westphal CH, Castillo PE, Chandra SS | title = Synucleins regulate the kinetics of synaptic vesicle endocytosis | journal = The Journal of Neuroscience| volume = 34 | issue = 28 | pages = 9364–9376 | date = July 2014 | pmid = 25009269 | pmc = 4087213 | doi = 10.1523/JNEUROSCI.4787-13.2014 }}</ref><ref>{{cite journal | vauthors = Wang L, Das U, Scott DA, Tang Y, McLean PJ, Roy S | title = α-synuclein multimers cluster synaptic vesicles and attenuate recycling | journal = Current Biology | volume = 24 | issue = 19 | pages = 2319–2326 | date = October 2014 | pmid = 25264250 | pmc = 4190006 | doi = 10.1016/j.cub.2014.08.027 | bibcode = 2014CBio...24.2319W }}</ref><ref name="Sun_2019">{{cite journal | vauthors = Sun J, Wang L, Bao H, Premi S, Das U, Chapman ER, Roy S | title = Functional cooperation of α-synuclein and VAMP2 in synaptic vesicle recycling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 23 | pages = 11113–11115 | date = June 2019 | pmid = 31110017 | pmc = 6561242 | doi = 10.1073/pnas.1903049116 | bibcode = 2019PNAS..11611113S | doi-access = free }}</ref> An alternate view is that alpha-synuclein binds to [[VAMP2]] (a [[synaptobrevin]]) and stabilizes [[SNARE (protein)|SNARE complexes]];<ref name="Burre_2010" /><ref>{{cite journal | vauthors = Burré J, Sharma M, Südhof TC | title = Cell Biology and Pathophysiology of α-Synuclein | journal = Cold Spring Harbor Perspectives in Medicine | volume = 8 | issue = 3 | article-number = a024091 | date = March 2018 | pmid = 28108534 | pmc = 5519445 | doi = 10.1101/cshperspect.a024091 }}</ref><ref>{{cite journal | vauthors = Burré J, Sharma M, Südhof TC | title = Systematic mutagenesis of α-synuclein reveals distinct sequence requirements for physiological and pathological activities | journal = The Journal of Neuroscience| volume = 32 | issue = 43 | pages = 15227–15242 | date = October 2012 | pmid = 23100443 | pmc = 3506191 | doi = 10.1523/JNEUROSCI.3545-12.2012 }}</ref><ref>{{cite journal | vauthors = Burré J, Sharma M, Südhof TC | title = α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 40 | pages = E4274–E4283 | date = October 2014 | pmid = 25246573 | pmc = 4210039 | doi = 10.1073/pnas.1416598111 | doi-access = free | bibcode = 2014PNAS..111E4274B }}</ref><ref name="Diao_2013">{{cite journal | vauthors = Diao J, Burré J, Vivona S, Cipriano DJ, Sharma M, Kyoung M, Südhof TC, Brunger AT | title = Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2 | journal = eLife | volume = 2 | article-number = e00592 | date = April 2013 | pmid = 23638301 | pmc = 3639508 | doi = 10.7554/eLife.00592 | doi-access = free }}</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 break]]s (DSBs).<ref name="Schaser_2019">{{cite journal | vauthors = Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK | title = Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders | journal = Scientific Reports | volume = 9 | issue = 1 | article-number = 10919 | date = July 2019 | pmid = 31358782 | pmc = 6662836 | doi = 10.1038/s41598-019-47227-z | bibcode = 2019NatSR...910919S }}</ref> [[DNA damage (naturally occurring)|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 mouse|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-synuclein===
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>{{cite journal | vauthors = Ryskalin L, Busceti CL, Limanaqi F, Biagioni F, Gambardella S, Fornai F | title = A Focus on the Beneficial Effects of Alpha Synuclein and a Re-Appraisal of Synucleinopathies | journal = Current Protein & Peptide Science | volume = 19 | issue = 6 | pages = 598–611 | year = 2018 | pmid = 29150919 | pmc = 5925871 | doi = 10.2174/1389203718666171117110028 }}</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>{{cite journal | vauthors = Micheli L, Creanza TM, Ceccarelli M, D'Andrea G, Giacovazzo G, Ancona N, Coccurello R, Scardigli R, Tirone F | title = Transcriptome Analysis in a Mouse Model of Premature Aging of Dentate Gyrus: Rescue of Alpha-Synuclein Deficit by Virus-Driven Expression or by Running Restores the Defective Neurogenesis | journal = Frontiers in Cell and Developmental Biology | volume = 9 | article-number = 696684 | year = 2021 | pmid = 34485283 | pmc = 8415876 | doi = 10.3389/fcell.2021.696684 | doi-access = free }}</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>{{cite journal | vauthors = Perez-Villalba A, Sirerol-Piquer MS, Belenguer G, Soriano-Cantón R, Muñoz-Manchado AB, Villadiego J, Alarcón-Arís D, Soria FN, Dehay B, Bezard E, Vila M, Bortolozzi A, Toledo-Aral JJ, Pérez-Sánchez F, Fariñas I | title = Synaptic Regulator α-Synuclein in Dopaminergic Fibers Is Essentially Required for the Maintenance of Subependymal Neural Stem Cells | journal = The Journal of Neuroscience| volume = 38 | issue = 4 | pages = 814–825 | date = January 2018 | pmid = 29217686 | pmc = 6596232 | doi = 10.1523/JNEUROSCI.2276-17.2017 }}</ref>

== Sequence ==

Alpha-synuclein [[primary structure]] is usually divided in three distinct domains:
* Residues 1-60: An [[amphiphile|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>{{cite journal | vauthors = Clayton DF, George JM | title = The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease | journal = Trends in Neurosciences | volume = 21 | issue = 6 | pages = 249–254 | date = June 1998 | pmid = 9641537 | doi = 10.1016/S0166-2236(97)01213-7 | s2cid = 20654921 }}</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>{{cite journal | vauthors = Bussell R, Eliezer D | title = A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins | journal = Journal of Molecular Biology | volume = 329 | issue = 4 | pages = 763–778 | date = June 2003 | pmid = 12787676 | doi = 10.1016/S0022-2836(03)00520-5 }}</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>{{cite journal | vauthors = Uchihara T, Giasson BI | title = Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies | journal = Acta Neuropathologica | volume = 131 | issue = 1 | pages = 49–73 | date = January 2016 | pmid = 26446103 | pmc = 4698305 | doi = 10.1007/s00401-015-1485-1 }}</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 [[protein]]s.<ref>{{cite journal | vauthors = Sorrentino ZA, Xia Y, Gorion KM, Hass E, Giasson BI | title = Carboxy-terminal truncations of mouse α-synuclein alter aggregation and prion-like seeding | journal = FEBS Letters | volume = 594 | issue = 8 | pages = 1271–1283 | date = April 2020 | pmid = 31912891 | pmc = 7188589 | doi = 10.1002/1873-3468.13728 }}</ref><ref name="Burre_2010" />

== Autoproteolytic activity ==

The use of high-resolution [[Ion-mobility spectrometry–mass spectrometry|ion-mobility mass spectrometry]] (IMS-MS) on HPLC-purified alpha-synuclein ''in vitro'' has shown alpha-synuclein to be [[autoproteolytic]] (self-[[Proteolysis|proteolytic]]), generating a variety of small [[molecular weight]] fragments upon incubation.<ref name="Vlad_2011">{{cite journal | vauthors = Vlad C, Lindner K, Karreman C, Schildknecht S, Leist M, Tomczyk N, Rontree J, Langridge J, Danzer K, Ciossek T, Petre A, Gross ML, Hengerer B, Przybylski M | title = Autoproteolytic fragments are intermediates in the oligomerization/aggregation of the Parkinson's disease protein alpha-synuclein as revealed by ion mobility mass spectrometry | journal = ChemBioChem | volume = 12 | issue = 18 | pages = 2740–2744 | date = December 2011 | pmid = 22162214 | pmc = 3461308 | doi = 10.1002/cbic.201100569 }}</ref> The 14.46&nbsp;[[Kilodalton|kDa]] protein was found to generate numerous smaller fragments, including 12.16&nbsp;kDa ([[amino acids]] 14–133) and 10.44&nbsp;kDa (40–140) fragments formed through [[C-terminus|C-]] and [[N-terminus|N-terminal]] truncation and a 7.27 kDa C-terminal fragment (72–140). The 7.27&nbsp;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 significance ==

[[File:Lewy Body alphaSynuclein.jpg|thumb|Positive α-Synuclein staining of a [[Lewy body]] from a patient who had Parkinson's disease.]]
Alpha synuclein, having no single, well-defined tertiary structure, is an [[intrinsically disordered protein]],<ref>{{cite journal | vauthors = Chiti F, Dobson CM | title = Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade | journal = Annual Review of Biochemistry | volume = 86 | pages = 27–68 | date = June 2017 | pmid = 28498720 | doi = 10.1146/annurev-biochem-061516-045115 | hdl = 2158/1117236 | hdl-access = free }}</ref><ref name="Half a century of amyloids: past, p">{{cite journal | vauthors = Ke PC, Zhou R, Serpell LC, Riek R, Knowles TP, Lashuel HA, Gazit E, Hamley IW, Davis TP, Fändrich M, Otzen DE, Chapman MR, Dobson CM, Eisenberg DS, Mezzenga R | title = Half a century of amyloids: past, present and future | journal = Chemical Society Reviews | volume = 49 | issue = 15 | pages = 5473–5509 | date = August 2020 | pmid = 32632432 | pmc = 7445747 | doi = 10.1039/c9cs00199a }}</ref> with a pI value of 4.7,<ref>{{cite journal | vauthors = Furukawa K, Aguirre C, So M, Sasahara K, Miyanoiri Y, Sakurai K, Yamaguchi K, Ikenaka K, Mochizuki H, Kardos J, Kawata Y, Goto Y | title = Isoelectric point-amyloid formation of α-synuclein extends the generality of the solubility and supersaturation-limited mechanism | journal = Current Research in Structural Biology | volume = 2 | pages = 35–44 | date = 2020 | pmid = 34235468 | pmc = 8244297 | doi = 10.1016/j.crstbi.2020.03.001 }}</ref> which, under certain pathological conditions, can [[Proteinopathy|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>{{cite journal | vauthors = Theillet FX, Binolfi A, Frembgen-Kesner T, Hingorani K, Sarkar M, Kyne C, Li C, Crowley PB, Gierasch L, Pielak GJ, Elcock AH, Gershenson A, Selenko P | title = Physicochemical properties of cells and their effects on intrinsically disordered proteins (IDPs) | journal = Chemical Reviews | volume = 114 | issue = 13 | pages = 6661–6714 | date = July 2014 | pmid = 24901537 | pmc = 4095937 | doi = 10.1021/cr400695p }}</ref><ref>{{cite journal | vauthors = Eisenberg D, Jucker M | title = The amyloid state of proteins in human diseases | journal = Cell | volume = 148 | issue = 6 | pages = 1188–1203 | date = March 2012 | pmid = 22424229 | pmc = 3353745 | doi = 10.1016/j.cell.2012.02.022 }}</ref> In 2011, two groups published their findings that unmutated α-synuclein forms a stably folded tetramer that resists [[protein aggregation|aggregation]], asserting that this folded tetramer represented the relevant in vivo structure in cells,<ref name="Bartels_2011">{{cite journal | vauthors = Bartels T, Choi JG, Selkoe DJ | title = α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation | journal = Nature | volume = 477 | issue = 7362 | pages = 107–110 | date = August 2011 | pmid = 21841800 | pmc = 3166366 | doi = 10.1038/nature10324 | bibcode = 2011Natur.477..107B }}</ref><ref>{{cite journal | vauthors = Wang W, Perovic I, Chittuluru J, Kaganovich A, Nguyen LT, Liao J, Auclair JR, Johnson D, Landeru A, Simorellis AK, Ju S, Cookson MR, Asturias FJ, Agar JN, Webb BN, Kang C, Ringe D, Petsko GA, Pochapsky TC, Hoang QQ | title = A soluble α-synuclein construct forms a dynamic tetramer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 43 | pages = 17797–17802 | date = October 2011 | pmid = 22006323 | pmc = 3203798 | doi = 10.1073/pnas.1113260108 | bibcode = 2011PNAS..10817797W | doi-access = free }}</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">{{cite journal | vauthors = Dettmer U, Newman AJ, Luth ES, Bartels T, Selkoe D | title = In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells | journal = The Journal of Biological Chemistry | volume = 288 | issue = 9 | pages = 6371–6385 | date = March 2013 | pmid = 23319586 | pmc = 3585072 | doi = 10.1074/jbc.M112.403311 | doi-access = free }}</ref><ref name="Westphal_2013">{{cite journal | vauthors = Westphal CH, Chandra SS | title = Monomeric synucleins generate membrane curvature | journal = The Journal of Biological Chemistry | volume = 288 | issue = 3 | pages = 1829–1840 | date = January 2013 | pmid = 23184946 | pmc = 3548493 | doi = 10.1074/jbc.M112.418871 | doi-access = free }}</ref><ref name="Trexler_2012">{{cite journal | vauthors = Trexler AJ, Rhoades E | title = N-Terminal acetylation is critical for forming α-helical oligomer of α-synuclein | journal = Protein Science | volume = 21 | issue = 5 | pages = 601–605 | date = May 2012 | pmid = 22407793 | pmc = 3403458 | doi = 10.1002/pro.2056 }}</ref> However, despite numerous in-cell NMR reports demonstrating that alpha synuclein is indeed monomeric and disordered in intact [[E. coli]] cells,<ref>{{cite journal | vauthors = Binolfi A, Theillet FX, Selenko P | title = Bacterial in-cell NMR of human α-synuclein: a disordered monomer by nature? | journal = Biochemical Society Transactions | volume = 40 | issue = 5 | pages = 950–954 | date = October 2012 | pmid = 22988846 | doi = 10.1042/BST20120096 | url = https://hal.science/hal-04936650 }}</ref><ref>{{cite journal | vauthors = Bertini I, Felli IC, Gonnelli L, Vasantha Kumar MV, Pierattelli R | title = High-resolution characterization of intrinsic disorder in proteins: expanding the suite of (13)C-detected NMR spectroscopy experiments to determine key observables | journal = ChemBioChem | volume = 12 | issue = 15 | pages = 2347–2352 | date = October 2011 | pmid = 23106082 | doi = 10.1002/cbic.201100406 | s2cid = 34960247 }}</ref><ref>{{cite journal | vauthors = Waudby CA, Camilloni C, Fitzpatrick AW, Cabrita LD, Dobson CM, Vendruscolo M, Christodoulou J | title = In-cell NMR characterization of the secondary structure populations of a disordered conformation of α-synuclein within E. coli cells | journal = PLOS ONE | volume = 8 | issue = 8 | article-number = e72286 | date = 26 August 2013 | pmid = 23991082 | pmc = 3753296 | doi = 10.1371/journal.pone.0072286 | bibcode = 2013PLoSO...872286W | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li C, Liu M | title = Protein dynamics in living cells studied by in-cell NMR spectroscopy | journal = FEBS Letters | volume = 587 | issue = 8 | pages = 1008–1011 | date = April 2013 | pmid = 23318712 | doi = 10.1016/j.febslet.2012.12.023 | s2cid = 2649589 | doi-access = free | bibcode = 2013FEBSL.587.1008L }}</ref><ref name="Fauvet_2012" /><ref>{{cite journal | vauthors = Pérez AC, Subrini O, Hessel A, Ladant D, Chenal A | title = Molecular Crowding Stabilizes Both the Intrinsically Disordered Calcium-Free State and the Folded Calcium-Bound State of an RTX Protein: Implication for Toxin Secretion | journal = Biophysical Journal | volume = 106 | issue = 2 | pages = 271a | date = January 2014 | doi = 10.1016/j.bpj.2013.11.1589 | bibcode = 2014BpJ...106R.271S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Waudby CA, Mantle MD, Cabrita LD, Gladden LF, Dobson CM, Christodoulou J | title = Rapid distinction of intracellular and extracellular proteins using NMR diffusion measurements | journal = Journal of the American Chemical Society | volume = 134 | issue = 28 | pages = 11312–11315 | date = July 2012 | pmid = 22694283 | doi = 10.1021/ja304912c | bibcode = 2012JAChS.13411312W | url = https://discovery.ucl.ac.uk/id/eprint/1365837/ }}</ref><ref>{{cite journal | vauthors = Croke RL, Sallum CO, Watson E, Watt ED, Alexandrescu AT | title = Hydrogen exchange of monomeric alpha-synuclein shows unfolded structure persists at physiological temperature and is independent of molecular crowding in Escherichia coli | journal = Protein Science | volume = 17 | issue = 8 | pages = 1434–1445 | date = August 2008 | pmid = 18493022 | pmc = 2492816 | doi = 10.1110/ps.033803.107 }}</ref> it is still a matter of debate in the field despite an ever growing mountain of conflicting reports.<ref name="Fauvet_2012">{{cite journal | vauthors = Fauvet B, Mbefo MK, Fares MB, Desobry C, Michael S, Ardah MT, Tsika E, Coune P, Prudent M, Lion N, Eliezer D, Moore DJ, Schneider B, Aebischer P, El-Agnaf OM, Masliah E, Lashuel HA | title = α-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer | journal = The Journal of Biological Chemistry | volume = 287 | issue = 19 | pages = 15345–15364 | date = May 2012 | pmid = 22315227 | pmc = 3346117 | doi = 10.1074/jbc.M111.318949 | doi-access = free }}</ref><ref name="Burre_2013">{{cite journal | vauthors = Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC | title = Properties of native brain α-synuclein | journal = Nature | volume = 498 | issue = 7453 | pages = E4–6; discussion E6–7 | date = June 2013 | pmid = 23765500 | pmc = 4255827 | doi = 10.1038/nature12125 | bibcode = 2013Natur.498E...4B }}</ref><ref name="Theillet_2016">{{cite journal | vauthors = Theillet FX, Binolfi A, Bekei B, Martorana A, Rose HM, Stuiver M, Verzini S, Lorenz D, van Rossum M, Goldfarb D, Selenko P | title = Structural disorder of monomeric α-synuclein persists in mammalian cells | journal = Nature | volume = 530 | issue = 7588 | pages = 45–50 | date = February 2016 | pmid = 26808899 | doi = 10.1038/nature16531 | s2cid = 4461465 | bibcode = 2016Natur.530...45T | hdl = 11336/53199 | url = https://repository.publisso.de/resource/frl:6410667 | hdl-access = free }}</ref> Nevertheless, alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by [[Lewy body|Lewy bodies]], such as [[Parkinson's disease]], [[dementia with Lewy bodies]] and [[multiple system atrophy]].<ref name="Spillantini_1997">{{cite journal | vauthors = Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M | title = Alpha-synuclein in Lewy bodies | journal = Nature | volume = 388 | issue = 6645 | pages = 839–840 | date = August 1997 | pmid = 9278044 | doi = 10.1038/42166 | s2cid = 4419837 | bibcode = 1997Natur.388..839G | doi-access = free }}</ref><ref name="Mezey_1998">{{cite journal | vauthors = Mezey E, Dehejia A, Harta G, Papp MI, Polymeropoulos MH, Brownstein MJ | title = Alpha synuclein in neurodegenerative disorders: murderer or accomplice? | journal = Nature Medicine | volume = 4 | issue = 7 | pages = 755–757 | date = July 1998 | pmid = 9662355 | doi = 10.1038/nm0798-755 | s2cid = 46196799 | url = https://zenodo.org/record/1233447 }}</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>{{cite journal | vauthors = Marvian AT, Koss DJ, Aliakbari F, Morshedi D, Outeiro TF | title = In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies | journal = Journal of Neurochemistry | volume = 150 | issue = 5 | pages = 535–565 | date = September 2019 | pmid = 31004503 | doi = 10.1111/jnc.14707 | s2cid = 125080534 | doi-access = free }}</ref> Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain [[tau protein]];<ref name="pmid 10528110">{{cite journal | vauthors = Arima K, Hirai S, Sunohara N, Aoto K, Izumiyama Y, Uéda K, Ikeda K, Kawai M | title = Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies | journal = Brain Research | volume = 843 | issue = 1–2 | pages = 53–61 | date = October 1999 | pmid = 10528110 | doi = 10.1016/S0006-8993(99)01848-X | s2cid = 11144367 }}</ref> however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies.<ref name="Arima_2000">{{cite journal | vauthors = Arima K, Mizutani T, Alim MA, Tonozuka-Uehara H, Izumiyama Y, Hirai S, Uéda K | title = NACP/alpha-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies | journal = Acta Neuropathologica | volume = 100 | issue = 2 | pages = 115–121 | date = August 2000 | pmid = 10963357 | doi = 10.1007/s004010050002 | s2cid = 22950302 }}</ref> Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.<ref name="Yokota_2002">{{cite journal | vauthors = Yokota O, Terada S, Ishizu H, Ujike H, Ishihara T, Nakashima H, Yasuda M, Kitamura Y, Uéda K, Checler F, Kuroda S | title = NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases | journal = Acta Neuropathologica | volume = 104 | issue = 6 | pages = 637–648 | date = December 2002 | pmid = 12410385 | doi = 10.1007/s00401-002-0596-7 | s2cid = 42542929 }}</ref>

The aggregation mechanism of alpha-synuclein is uncertain. There is evidence of a structured intermediate rich in [[beta sheet|beta structure]] that can be the precursor of aggregation and, ultimately, Lewy bodies.<ref name="Kim_2007">{{cite journal | vauthors = Kim HY, Heise H, Fernandez CO, Baldus M, Zweckstetter M | title = Correlation of amyloid fibril beta-structure with the unfolded state of alpha-synuclein | journal = ChemBioChem | volume = 8 | issue = 14 | pages = 1671–1674 | date = September 2007 | pmid = 17722123 | doi = 10.1002/cbic.200700366 | s2cid = 41870508 }}</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">{{cite journal | vauthors = Sandal M, Valle F, Tessari I, Mammi S, Bergantino E, Musiani F, Brucale M, Bubacco L, Samorì B | title = Conformational equilibria in monomeric alpha-synuclein at the single-molecule level | journal = PLOS Biology | volume = 6 | issue = 1 | article-number = e6 | date = January 2008 | pmid = 18198943 | pmc = 2174973 | doi = 10.1371/journal.pbio.0060006 | doi-access = free }}</ref> One theory is that the majority of alpha-synuclein aggregates are located in the presynapse as smaller deposits which causes synaptic dysfunction.<ref>{{cite journal | vauthors = Schulz-Schaeffer WJ | title = The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia | journal = Acta Neuropathologica | volume = 120 | issue = 2 | pages = 131–143 | date = August 2010 | pmid = 20563819 | pmc = 2892607 | doi = 10.1007/s00401-010-0711-0 }}</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>{{cite journal | vauthors = Morshedi D, Aliakbari F | title = The Inhibitory Effects of Cuminaldehyde on Amyloid Fibrillation and Cytotoxicity of Alpha-synuclein | journal = Modares Journal of Medical Sciences: Pathobiology | volume = 15 | issue = 1 | pages = 45–60 | date = Spring 2012 }}</ref>
The [[Epstein-Barr virus]] has been implicated in these disorders.<ref>{{cite journal | vauthors = Woulfe J, Hoogendoorn H, Tarnopolsky M, Muñoz DG | title = Monoclonal antibodies against Epstein-Barr virus cross-react with alpha-synuclein in human brain | journal = Neurology | volume = 55 | issue = 9 | pages = 1398–1401 | date = November 2000 | pmid = 11087792 | doi = 10.1212/WNL.55.9.1398 | s2cid = 84387269 }}</ref>

In rare cases of familial forms of [[Parkinson's disease]], there is a mutation in the [[gene]] coding for alpha-synuclein. Five [[point mutation]]s have been identified thus far: [[A53T Mutation|A53T]],<ref name="Polymeropoulos_1997">{{cite journal | vauthors = Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL | title = Mutation in the alpha-synuclein gene identified in families with Parkinson's disease | journal = Science | location = New York, N.Y. | volume = 276 | issue = 5321 | pages = 2045–2047 | date = June 1997 | pmid = 9197268 | doi = 10.1126/science.276.5321.2045 | url = https://zenodo.org/record/1231112 }}</ref> A30P,<ref name="Kruger_1998">{{cite journal | vauthors = Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O | title = Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease | journal = Nature Genetics | volume = 18 | issue = 2 | pages = 106–108 | date = February 1998 | pmid = 9462735 | doi = 10.1038/ng0298-106 | s2cid = 40777043 }}</ref> E46K,<ref name="Zarranz_2004">{{cite journal | vauthors = Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz DG, de Yebenes JG | title = The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia | journal = Annals of Neurology | volume = 55 | issue = 2 | pages = 164–173 | date = February 2004 | pmid = 14755719 | doi = 10.1002/ana.10795 | s2cid = 55263 }}</ref> H50Q,<ref name="AppelCresswell_2013">{{cite journal | vauthors = Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, Weir D, Thompson C, Szu-Tu C, Trinh J, Aasly JO, Rajput A, Rajput AH, Jon Stoessl A, Farrer MJ | title = Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease | journal = Movement Disorders| volume = 28 | issue = 6 | pages = 811–813 | date = June 2013 | pmid = 23457019 | doi = 10.1002/mds.25421 | s2cid = 13508258 }}</ref> and G51D;<ref name="Lesage_2013">{{cite journal | vauthors = Lesage S, Anheim M, Letournel F, Bousset L, Honoré A, Rozas N, Pieri L, Madiona K, Dürr A, Melki R, Verny C, Brice A | title = G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome | journal = Annals of Neurology | volume = 73 | issue = 4 | pages = 459–471 | date = April 2013 | pmid = 23526723 | doi = 10.1002/ana.23894 | s2cid = 43305127 }}</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>{{cite journal | vauthors = Fevga C, Park Y, Lohmann E, Kievit AJ, Breedveld GJ, Ferraro F, de Boer L, van Minkelen R, Hanagasi H, Boon A, Wang W, Petsko GA, Hoang QQ, Emre M, Bonifati V | title = A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease | journal = Parkinsonism & Related Disorders | volume = 89 | pages = 63–72 | date = August 2021 | pmid = 34229155 | pmc = 8607441 | doi = 10.1016/j.parkreldis.2021.06.023 }}</ref>

It has been reported that some mutations influence the initiation and amplification steps of the aggregation process.<ref>{{cite journal | vauthors = Giasson BI, Uryu K, Trojanowski JQ, Lee VM | title = Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro | journal = The Journal of Biological Chemistry | volume = 274 | issue = 12 | pages = 7619–7622 | date = March 1999 | pmid = 10075647 | doi = 10.1074/jbc.274.12.7619 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Flagmeier P, Meisl G, Vendruscolo M, Knowles TP, Dobson CM, Buell AK, Galvagnion C | title = Mutations associated with familial Parkinson's disease alter the initiation and amplification steps of α-synuclein aggregation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 37 | pages = 10328–10333 | date = September 2016 | pmid = 27573854 | pmc = 5027465 | doi = 10.1073/pnas.1604645113 | bibcode = 2016PNAS..11310328F | doi-access = free }}</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">{{cite journal | vauthors = Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K | title = alpha-Synuclein locus triplication causes Parkinson's disease | journal = Science | location = New York, N.Y. | volume = 302 | issue = 5646 | page = 841 | date = October 2003 | pmid = 14593171 | doi = 10.1126/science.1090278 | s2cid = 85938327 | url = https://zenodo.org/record/1230840 }}</ref><ref name="ChartierHarlin_2004">{{cite journal | vauthors = Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destée A | title = Alpha-synuclein locus duplication as a cause of familial Parkinson's disease | journal = Lancet | location = London, England | volume = 364 | issue = 9440 | pages = 1167–1169 | date = 2004 | pmid = 15451224 | doi = 10.1016/S0140-6736(04)17103-1 | s2cid = 54419671 }}</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>{{cite journal | vauthors = Eslamboli A, Romero-Ramos M, Burger C, Bjorklund T, Muzyczka N, Mandel RJ, Baker H, Ridley RM, Kirik D | title = Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain | journal = Brain  | volume = 130 | issue = Pt 3 | pages = 799–815 | date = March 2007 | pmid = 17303591 | doi = 10.1093/brain/awl382 | doi-access = free }}</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>{{Cite journal | vauthors = Oh SE, Mouradian MM, Barker E, Grosso Jasutkar H | title = Therapeutics in the Pipeline Targeting α-Synuclein for Parkinson's Disease | journal = Pharmacological Reviews | volume = 74 | issue = 1 | pages = 207–237 | date = 2022-01-01 | pmid = 35017177 | pmc = 11034868 | doi = 10.1124/pharmrev.120.000133 | language = en }}</ref> Research indicates that [[MIR7-1|microRNA-7]] and the naturally occurring small molecule [[quercetin]] can reduce alpha-synuclein levels under experimental conditions.<ref>{{Cite journal | vauthors = Choudhury NR, Rooney S, Pham NT, Koszela J, Kelly D, Spanos C, Rappsilber J, Auer M, Michlewski G, Zhu S | title = RNA pull-down confocal nanoscanning (RP-CONA) detects quercetin as pri-miR-7/HuR interaction inhibitor that decreases α-synuclein levels | journal = Nucleic Acids Research | volume = 49 | issue = 11 | pages = 6456–6473 | date = 2021-06-21 | pmid = 34107032 | pmc = 8216281 | doi = 10.1093/nar/gkab484 | url = https://academic.oup.com/nar/article/49/11/6456/6295535 | language = en | issn = 0305-1048 }}</ref>

Certain sections of the alpha-synuclein protein may play a role in the [[tauopathies]].<ref>{{cite journal | vauthors = Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM | title = Initiation and synergistic fibrillization of tau and alpha-synuclein | journal = Science | location = New York, N.Y. | volume = 300 | issue = 5619 | pages = 636–640 | date = April 2003 | pmid = 12714745 | doi = 10.1126/science.1082324 | s2cid = 20223000 | bibcode = 2003Sci...300..636G }}</ref><ref name="Takeda_2000">{{cite journal | vauthors = Takeda A, Hashimoto M, Mallory M, Sundsumo M, Hansen L, Masliah E | title = C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders | journal = Acta Neuropathologica | volume = 99 | issue = 3 | pages = 296–304 | date = March 2000 | pmid = 10663973 | doi = 10.1007/PL00007441 | s2cid = 27393027 }}</ref><ref>{{cite journal | vauthors = Williams T, Sorrentino Z, Weinrich M, Giasson BI, Chakrabarty P | title = Differential cross-seeding properties of tau and α-synuclein in mouse models of tauopathy and synucleinopathy | journal = Brain Communications | volume = 2 | issue = 2 | article-number = fcaa090 | date = 2020-07-01 | pmid = 33094280 | pmc = 7567170 | doi = 10.1093/braincomms/fcaa090 }}</ref>

A [[prion]] form of the protein alpha-synuclein may be a causal agent for the disease [[multiple system atrophy]].<ref>{{cite journal | vauthors = Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K | title = Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 38 | pages = E5308–E5317 | date = September 2015 | pmid = 26324905 | pmc = 4586853 | doi = 10.1073/pnas.1514475112 | doi-access = free | bibcode = 2015PNAS..112E5308P }}</ref><ref>{{cite web | vauthors = Weiler N | title = New Type of Prion May Cause, Transmit Neurodegeneration | date = 31 August 2015 | url = http://www.ucsf.edu/news/2015/08/131416/new-type-prion-may-cause-transmit-neurodegeneration }}</ref><ref>{{cite journal | vauthors = Rettner R | title = Another Fatal Brain Disease May Come from the Spread of 'Prion' Proteins | journal = Wired Science | date = 31 August 2015 | url = http://www.livescience.com/52040-prions-multiple-system-atrophy.html }}</ref>

[[File:Events in alpha synuclein toxicity.jpg|thumb|Events in α-synuclein toxicity.<ref name="Cookson_2009">{{cite journal | vauthors = Cookson MR | title = alpha-Synuclein and neuronal cell death | journal = Molecular Neurodegeneration | volume = 4 | issue = 1 | page = 9 | date = February 2009 | pmid = 19193223 | pmc = 2646729 | doi = 10.1186/1750-1326-4-9 | doi-access = free }}</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>{{cite journal | vauthors = De Giorgi F, Laferrière F, Zinghirino F, Faggiani E, Lends A, Bertoni M, Yu X, Grélard A, Morvan E, Habenstein B, Dutheil N, Doudnikoff E, Daniel J, Claverol S, Qin C, Loquet A, Bezard E, Ichas F | title = Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons | journal = Science Advances | volume = 6 | issue = 40 | article-number = eabc4364 | date = October 2020 | pmid = 33008896 | pmc = 7852382 | doi = 10.1126/sciadv.abc4364 | bibcode = 2020SciA....6.4364D }}</ref> {{More citations needed section|date=November 2015}}
[[Antibodies]] against alpha-synuclein have replaced antibodies against [[ubiquitin]] as the gold standard for [[immunostaining]] of Lewy bodies.<ref>{{cite journal | vauthors = Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T | title = alpha-Synuclein is phosphorylated in synucleinopathy lesions | journal = Nature Cell Biology | volume = 4 | issue = 2 | pages = 160–164 | date = February 2002 | pmid = 11813001 | doi = 10.1038/ncb748 | s2cid = 40155547 }}</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, allowing small molecules to be translocated from one side of the membrane to the other through the hollow oligomer.<ref>{{cite journal | vauthors = Brøchner BV, Zhang X, Nielsen J, Kjems J, Otzen DE, Malle MG | title = Single-vesicle Tracking of α-Synuclein Oligomers Reveals Pore Formation by a Three-Stage Model | journal = ACS Nano | date = August 2025 | pmid = 40794544 | doi = 10.1021/acsnano.5c04005 | pmc = 12444998 }}</ref> 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 [[Serine|Ser]]129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as [[calpain]]s, 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 interactions ==

Alpha-synuclein has been shown to [[Protein-protein interaction|interact]] with
* [[Dopamine transporter]],<ref name="Wersinger_2003">{{cite journal | vauthors = Wersinger C, Sidhu A | title = Attenuation of dopamine transporter activity by alpha-synuclein | journal = Neuroscience Letters | volume = 340 | issue = 3 | pages = 189–192 | date = April 2003 | pmid = 12672538 | doi = 10.1016/S0304-3940(03)00097-1 | s2cid = 54381509 }}</ref><ref name="Lee_2001">{{cite journal | vauthors = Lee FJ, Liu F, Pristupa ZB, Niznik HB | title = Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis | journal = FASEB Journal| volume = 15 | issue = 6 | pages = 916–926 | date = April 2001 | pmid = 11292651 | doi = 10.1096/fj.00-0334com | doi-access = free | s2cid = 3406798 }}</ref>
* [[Parkin (ligase)]],<ref name="Choi_2001">{{cite journal | vauthors = Choi P, Golts N, Snyder H, Chong M, Petrucelli L, Hardy J, Sparkman D, Cochran E, Lee JM, Wolozin B | title = Co-association of parkin and alpha-synuclein | journal = NeuroReport | volume = 12 | issue = 13 | pages = 2839–2843 | date = September 2001 | pmid = 11588587 | doi = 10.1097/00001756-200109170-00017 | author10-link = Benjamin Wolozin | s2cid = 83941655 }}</ref><ref name="Kawahara_2008">{{cite journal | vauthors = Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H, Rockenstein E, Imam SZ, Masliah E | title = alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease | journal = The Journal of Biological Chemistry | volume = 283 | issue = 11 | pages = 6979–6987 | date = March 2008 | pmid = 18195004 | doi = 10.1074/jbc.M710418200 | doi-access = free }}</ref>
* [[Phospholipase D1]],<ref name="Ahn_2002">{{cite journal | vauthors = Ahn BH, Rhim H, Kim SY, Sung YM, Lee MY, Choi JY, Wolozin B, Chang JS, Lee YH, Kwon TK, Chung KC, Yoon SH, Hahn SJ, Kim MS, Jo YH, Min DS | title = alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 14 | pages = 12334–12342 | date = April 2002 | pmid = 11821392 | doi = 10.1074/jbc.M110414200 | s2cid = 85695661 | doi-access = free }}</ref>
* [[SNCAIP]],<ref name="Neystat_2002">{{cite journal | vauthors = Neystat M, Rzhetskaya M, Kholodilov N, Burke RE | title = Analysis of synphilin-1 and synuclein interactions by yeast two-hybrid beta-galactosidase liquid assay | journal = Neuroscience Letters | volume = 325 | issue = 2 | pages = 119–123 | date = June 2002 | pmid = 12044636 | doi = 10.1016/S0304-3940(02)00253-7 | s2cid = 11517781 }}</ref><ref name="Reed_1991">{{cite journal | vauthors = Reed JC, Meister L, Tanaka S, Cuddy M, Yum S, Geyer C, Pleasure D | title = Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin | journal = Cancer Research | volume = 51 | issue = 24 | pages = 6529–6538 | date = December 1991 | pmid = 1742726 }}</ref><ref name="Kawamata_2001">{{cite journal | vauthors = Kawamata H, McLean PJ, Sharma N, Hyman BT | title = Interaction of alpha-synuclein and synphilin-1: effect of Parkinson's disease-associated mutations | journal = Journal of Neurochemistry | volume = 77 | issue = 3 | pages = 929–934 | date = May 2001 | pmid = 11331421 | doi = 10.1046/j.1471-4159.2001.00301.x | s2cid = 83885937 | doi-access = free }}</ref><ref name="Engelender_1999">{{cite journal | vauthors = Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM, Ross CA | title = Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions | journal = Nature Genetics | volume = 22 | issue = 1 | pages = 110–114 | date = May 1999 | pmid = 10319874 | doi = 10.1038/8820 | author12-link = Ted M. Dawson | s2cid = 2611127 }}</ref>
* [[Tau protein]].<ref>{{cite journal | vauthors = Lee VM, Giasson BI, Trojanowski JQ | title = More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases | journal = Trends in Neurosciences | volume = 27 | issue = 3 | pages = 129–134 | date = March 2004 | pmid = 15036877 | doi = 10.1016/j.tins.2004.01.007 | s2cid = 9545889 }}</ref><ref name="Jensen_1999">{{cite journal | vauthors = Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R | title = alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 36 | pages = 25481–25489 | date = September 1999 | pmid = 10464279 | doi = 10.1074/jbc.274.36.25481 | s2cid = 23877061 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Giasson BI, Lee VM, Trojanowski JQ | title = Interactions of amyloidogenic proteins | journal = Neuromolecular Medicine | volume = 4 | issue = 1–2 | pages = 49–58 | year = 2003 | pmid = 14528052 | doi = 10.1385/NMM:4:1-2:49 | s2cid = 9086733 }}</ref>
* [[Beta amyloid]]<ref name="Ono_2012">{{cite journal | vauthors = Ono K, Takahashi R, Ikeda T, Yamada M | title = Cross-seeding effects of amyloid β-protein and α-synuclein | journal = Journal of Neurochemistry | volume = 122 | issue = 5 | pages = 883–890 | date = September 2012 | pmid = 22734715 | doi = 10.1111/j.1471-4159.2012.07847.x | s2cid = 17593306 | hdl = 2297/34736 | url = https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=13927&item_no=1&attribute_id=26&file_no=1 | doi-access = free }}</ref>

== See also ==
* [[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]]

== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin}}
* {{cite web | vauthors = Blakeslee S | title = In Folding Proteins, Clues to Many Diseases | date = 2002-05-27 | url = https://www.nytimes.com/2002/05/21/health/in-folding-proteins-clues-to-many-diseases.html | work = New York Times }}
* {{cite journal | vauthors = Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LM, Hutten SJ, Sherer T, Marek K, Soto C | title = Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study | journal = The Lancet. Neurology | volume = 22 | issue = 5 | pages = 407–417 | date = May 2023 | pmid = 37059509 | pmc = 10627170 | doi = 10.1016/S1474-4422(23)00109-6 | s2cid = 258083747 }}
{{refend}}

== External links ==
* {{commons-inline}}
* {{MeshName|alpha-Synuclein}}
* {{UCSC gene info|SNCA}}

{{PDB Gallery|geneid=6622}}
{{Nerve tissue protein}}

[[Category:Membrane channels]]
[[Category:Peripheral membrane proteins]]
[[Category:Lewy body dementia]]