View source for Alpha-synuclein

{{Infobox gene}}
'''Alpha-synuclein''' is a [[protein]] that, in humans, is encoded by the ''SNCA'' [[gene]].<ref name="ghrsnca">{{cite web | url=http://ghr.nlm.nih.gov/gene/SNCA | title = Genetics Home Reference: SNCA | publisher = U.S. National Library of Medicine | access-date = 14 Nov 2013 | date = 12 Nov 2013}}</ref> It is abundant in the brain while smaller amounts are found in the heart, muscles, and other tissues. In the brain, alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called [[presynaptic terminal]]s.<ref name="ghrsnca"/> Within these structures, alpha-synuclein 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 = 15313–8 | date = April 2003 | pmid = 12586824 | doi = 10.1074/jbc.M213128200 }}</ref> and proteins.<ref name="ghrsnca"/> Presynaptic terminals release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function.<ref name="ghrsnca"/>

Although the function of alpha-synuclein is not well understood, studies suggest that it plays a role in maintaining a supply of synaptic vesicles in presynaptic terminals by clustering synaptic vesicles.<ref name="pmid23638301">{{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 | issue =  | pages = e00592 | date = April 2013 | pmid = 23638301 | pmc = 3639508 | doi = 10.7554/eLife.00592 }}</ref> 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"/>

The human alpha-synuclein protein is made of 140 amino acids and is encoded by the ''SNCA'' [[gene]].<ref name="pmid8248242">{{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 = 11282–6 | date = December 1993 | pmid = 8248242 | pmc = 47966 | doi = 10.1073/pnas.90.23.11282 }}</ref><ref name="pmid12214035">{{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 =  | url = http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | archive-url = https://arquivo.pt/wayback/20160514170300/http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | dead-url = yes | 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. Alzheimers Dis. | volume = 4 | issue = 4 | pages = 337 | year = 2002 | pmid =  | doi =  | url = http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | archive-url = https://arquivo.pt/wayback/20160514170300/http://iospress.metapress.com/content/jpmvj4dubjpm3b73/ | dead-url = yes | archive-date = 2016-05-14 | issn =  }}</ref> An alpha-synuclein fragment, known as the non-[[Abeta]] component (NAC) of [[Alzheimer's disease]] [[amyloid]], originally found in an amyloid-enriched fraction, was shown to be a fragment of its precursor protein, NACP.<ref name="pmid8248242"/>  It was later determined that NACP was the human homologue of ''[[Torpedo (genus)|Torpedo]]'' synuclein. Therefore, NACP is now referred to as human alpha-synuclein.

== Tissue expression ==

Alpha-synuclein is a [[synuclein]] [[protein]] of unknown function primarily found in [[neural tissue]], making up as much as 1% of all proteins in the [[cytosol]] of brain cells.<ref name="pmid7857654">{{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 = 467–75 | date = February 1995 | pmid = 7857654 | doi = 10.1016/0896-6273(95)90302-X }}</ref> It is predominantly expressed in the [[neocortex]], [[hippocampus]], [[substantia nigra]], [[thalamus]], and [[cerebellum]].  It is predominantly a neuronal protein, but can also be found in the neuroglial cells.{{Citation needed|date=March 2012}} In melanocytic cells, SNCA protein expression may be regulated by [[Microphthalmia-associated transcription factor|MITF]].<ref name="pmid19067971">{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 665–76 | date = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x }}</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="pmid17275196">{{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 = 539–55 | date = March 2007 | pmid = 17275196 | doi = 10.1016/j.neuroscience.2006.12.028 }}</ref> Synuclein is however found predominantly in the [[presynaptic]] termini, in both free or membrane-bound forms,<ref name="pmid10722726">{{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 = 8812–6 | date = March 2000 | pmid = 10722726 | doi = 10.1074/jbc.275.12.8812 }}</ref> with roughly 15% of synuclein being membrane-bound in any moment in neurons.<ref name="pmid11679584">{{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 = 671–8 | date = January 2002 | pmid = 11679584 | doi = 10.1074/jbc.M107045200 }}</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 | issue =  | pages = 40–52 | date = December 2008 | pmid = 18817762 | doi = 10.1016/j.brainres.2008.08.067 }}</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 = 187–92 | date = May 2009 | pmid = 19429081 | doi = 10.1016/j.neulet.2009.02.056 }}</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 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 = 237–51 | date = September 2006 | pmid = 16845533 | doi = 10.1007/s00401-006-0104-6 }}</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 = 1366–72 | date = December 1994 | pmid = 7802671 | doi = 10.1006/bbrc.1994.2816 }}</ref> which lacks residue 103-130 due to loss of exon 5.<ref name="Beyer_2006"/>

== Structure ==

Alpha-synuclein in solution is considered to be an [[intrinsically disordered protein]], i.e. it lacks a single stable 3D structure.<ref name="pmid19837084" >{{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 = 826–33 | date = December 2009 | pmid = 19837084 | doi = 10.1016/j.jmb.2009.10.021 }}</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="pmid24475132">{{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 | pages = e86495 | date = January 2014 | pmid = 24475132 | pmc = 3901707 | doi = 10.1371/journal.pone.0086495 }}</ref>

== Function ==

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="pmid7646890">{{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 = 361–72 | date = August 1995 | pmid = 7646890 | doi = 10.1016/0896-6273(95)90040-3 }}</ref>
It has been shown that alpha-synuclein significantly interacts with [[tubulin]],<ref name="pmid11867079">{{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 = 2112–7 | date = January 2002 | pmid = 11698390 | pmc =  | doi = 10.1074/jbc.M102981200 }}</ref> and that alpha-synuclein may have activity as a potential microtubule-associated protein, like [[Tau protein|tau]].<ref name="pmid15345814">{{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 =  }}</ref>

Recent evidence suggests that alpha-synuclein functions as a molecular [[chaperone (protein)|chaperone]] in the formation of [[SNARE (protein)|SNARE]] complexes.<ref name="pmid16269324">{{cite journal | vauthors = Bonini NM, Giasson BI | title = Snaring the function of alpha-synuclein | journal = Cell | volume = 123 | issue = 3 | pages = 359–61 | date = November 2005 | pmid = 16269324 | doi = 10.1016/j.cell.2005.10.017 }}</ref><ref name="pmid16269331">{{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 = 383–96 | date = November 2005 | pmid = 16269331 | doi = 10.1016/j.cell.2005.09.028 }}</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="pmid20798282">{{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 | volume = 329 | issue = 5999 | pages = 1663–7 | date = September 2010 | pmid = 20798282 | pmc = 3235365 | doi = 10.1126/science.1195227 }}</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="aacooper">{{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 | volume = 313 | issue = 5785 | pages = 324–8 | date = July 2006 | pmid = 16794039 | pmc = 1983366 | doi = 10.1126/science.1129462 }}</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="pmid22469626">{{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 = 226–30 | date = May 2012 | pmid = 22469626 | pmc =  | doi = 10.1016/j.bbr.2012.03.026 }}</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 play a role in alpha-synuclein toxicity.<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 | volume = 302 | issue = 5651 | pages = 1769–72 | date = December 2003 | pmid = 14657499 | doi = 10.1126/science.1090389 }}</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 }}</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 = 19666–71 | date = December 2008 | pmid = 19066219 | pmc = 2605001 | doi = 10.1073/pnas.0807826105 }}</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 = 40186–97 | date = October 2003 | pmid = 12885775 | doi = 10.1074/jbc.M305326200 }}</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 = 5783–92 | 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="pmid20693280">{{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 = 32486–93 | date = October 2010 | pmid = 20693280 | pmc = 2952250 | doi = 10.1074/jbc.M110.139576 }}</ref> Using [[cryo-EM]] it was shown that these are micellar tubes of ~5-6&nbsp;nm diameter.<ref name="pmid22767608">{{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 = 29301–11 | date = August 2012 | pmid = 22767608 | pmc = 3436199 | doi = 10.1074/jbc.M112.365817 }}</ref>  Alpha-synuclein has also been shown to form lipid disc-like particles similar to [[apolipoproteins]].<ref name="pmid23609437">{{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 = 17620–30 | date = June 2013 | pmid = 23609437 | pmc = 3682563 | doi = 10.1074/jbc.M113.476697 }}</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 | volume = 280 | pages = 127–139 | date = July 2017 | pmid = 28579098 | doi = 10.1016/j.jmr.2017.02.014 }}</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 = 8135–42 | 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 | volume = 1860 | issue = 9 | pages = 1863–1875 | date = April 2018 | pmid = 29702073 | 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 = 2+ Influx into Lipid Vesicles Induced by Protein Aggregates | journal = Angewandte Chemie | 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 = 583–95 | date = February 2003 | pmid = 12597857 | doi = 10.1016/s0896-6273(03)00024-2 }}</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 = 223–33 | date = August 2006 | pmid = 16733698 | doi = 10.1007/s00221-006-0539-y }}</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 = 420–8 | 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 = 582–9 | date = May 2015 | pmid = 25580849 | pmc = 4471127 | doi = 10.1111/jnc.13024 }}</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 | year=1998 | doi = 10.1016/S0166-2236(97)01213-7}}</ref>
* Residues 61-95: A central hydrophobic region which includes the ''non-amyloid-β component'' (NAC) region, involved in protein aggregation<ref name="pmid8248242"/>
* Residues 96-140: a highly acidic and [[proline]]-rich region which has no distinct structural propensity

== 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="pmid22162214">{{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 = 2740–4 | date = December 2011 | pmid = 22162214 | pmc = 3461308 | doi = 10.1002/cbic.201100569 }}</ref> The 14.46 [[Kilodalton|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-terminus|C-]] and [[N-terminus|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 significance ==

[[File:Lewy Body alphaSynuclein.jpg|thumb|Positive α-Synuclein staining of a [[Lewy body]] from a patient who had Parkinson's disease.]]
Classically considered an [[Intrinsically unstructured proteins|unstructured]] soluble protein, unmutated α-synuclein forms a stably folded [[tetramer]] that resists [[protein aggregation|aggregation]].<ref name="pmid21841800">{{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 = 107–10 | date = August 2011 | pmid = 21841800 | pmc = 3166366 | doi = 10.1038/nature10324 | laysummary = http://www.focushms.com/features/new-clue-to-parkinsons/ | laysource = Harvard Medical School New Focus }}</ref> This observation, though reproduced and extended by several labs,<ref name="DettmerNewman2013">{{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 = 6371–85 | date = March 2013 | pmid = 23319586 | pmc = 3585072 | doi = 10.1074/jbc.M112.403311 }}</ref><ref name="WestphalChandra2012">{{cite journal | vauthors = Westphal CH, Chandra SS | title = Monomeric synucleins generate membrane curvature | journal = The Journal of Biological Chemistry | volume = 288 | issue = 3 | pages = 1829–40 | date = January 2013 | pmid = 23184946 | pmc = 3548493 | doi = 10.1074/jbc.M112.418871 }}</ref><ref name="TrexlerRhoades2012">{{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 = 601–5 | date = May 2012 | pmid = 22407793 | pmc = 3403458 | doi = 10.1002/pro.2056 }}</ref> is still a matter of debate in the field due to conflicting reports.<ref name="FauvetMbefo2012">{{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 = 15345–64 | date = May 2012 | pmid = 22315227 | pmc = 3346117 | doi = 10.1074/jbc.M111.318949 }}</ref><ref name="BurréVivona2013">{{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 }}</ref><ref name="TheilletBinolfi2016">{{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 }}</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|multiple system atrophy]].<ref name="pmid9278044">{{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 = 839–40 | date = August 1997 | pmid = 9278044 | pmc =  | doi = 10.1038/42166 }}</ref><ref name="pmid9662355">{{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 = 755–7 | date = July 1998 | pmid = 9662355 | pmc =  | doi = 10.1038/nm0798-755 }}</ref> These disorders are known as [[synucleinopathies]]. 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 }}</ref> however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies.<ref name="pmid10963357">{{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 = 115–21 | date = August 2000 | pmid = 10963357 | doi = 10.1007/s004010050002 }}</ref>  Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.<ref name="pmid12410385">{{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 = 637–48 | date = December 2002 | pmid = 12410385 | doi = 10.1007/s00401-002-0596-7 }}</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="pmid17722123">{{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 = 1671–4 | date = September 2007 | pmid = 17722123 | doi = 10.1002/cbic.200700366 }}</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="pmid18198943">{{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 | pages = e6 | date = January 2008 | pmid = 18198943 | pmc = 2174973 | doi = 10.1371/journal.pbio.0060006 }}</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 = 131–43 | 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 | pmid = | doi = | url = | issn = }}</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 = 1398–401 | date = November 2000 | pmid = 11087792 | doi = 10.1212/WNL.55.9.1398 }}</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="pmid9197268">{{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 | volume = 276 | issue = 5321 | pages = 2045–7 | date = June 1997 | pmid = 9197268 | pmc =  | doi = 10.1126/science.276.5321.2045 }}</ref> A30P,<ref name="pmid9462735">{{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 = 106–8 | date = February 1998 | pmid = 9462735 | pmc =  | doi = 10.1038/ng0298-106 }}</ref> E46K,<ref name="pmid14755719">{{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 = 164–73 | date = February 2004 | pmid = 14755719 | doi = 10.1002/ana.10795 }}</ref> H50Q,<ref name="pmid23457019">{{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 = 811–3 | date = June 2013 | pmid = 23457019 | doi = 10.1002/mds.25421 }}</ref> and G51D.<ref name="pmid23526723">{{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 = 459–71 | date = April 2013 | pmid = 23526723 | doi = 10.1002/ana.23894 }}</ref> It has been reported that some mutations influence the initiation and amplification steps of the aggregation process.<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 = 10328–33 | date = September 2016 | pmid = 27573854 | pmc = 5027465 | doi = 10.1073/pnas.1604645113 }}</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="pmid14593171">{{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 | volume = 302 | issue = 5646 | pages = 841 | date = October 2003 | pmid = 14593171 | doi = 10.1126/science.1090278 }}</ref> Hence certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to Parkinson's disease.

Certain sections of the alpha-synuclein protein may play a role in the [[tauopathies]].<ref name="pmid10663973">{{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 }}</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 = E5308-17 | date = September 2015 | pmid = 26324905 | pmc = 4586853 | doi = 10.1073/pnas.1514475112 }}</ref><ref>{{cite web | url = http://www.ucsf.edu/news/2015/08/131416/new-type-prion-may-cause-transmit-neurodegeneration | title = New Type of Prion May Cause, Transmit Neurodegeneration | first = Nicholas | last = Weiler | name-list-format = vanc | date = 31 August 2015 }}</ref><ref>{{cite journal | url = http://www.livescience.com/52040-prions-multiple-system-atrophy.html | title = Another Fatal Brain Disease May Come from the Spread of 'Prion' Proteins | work = Wired Science | first = Rachael | last = Rettner | name-list-format = vanc | date = 31 August 2015 }}</ref>

[[File:Events in alpha synuclein toxicity.jpg|thumb|Events in α-synuclein toxicity.<ref name="pmid19193223">{{cite journal | vauthors = Cookson MR | title = alpha-Synuclein and neuronal cell death | journal = Molecular Neurodegeneration | volume = 4 | issue = 1 | pages = 9 | date = February 2009 | pmid = 19193223 | pmc = 2646729 | doi = 10.1186/1750-1326-4-9 }}</ref>]]
{{Refimprove 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 = 160–4 | date = February 2002 | pmid = 11813001 | doi = 10.1038/ncb748 }}</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 interactions ==

Alpha-synuclein has been shown to [[Protein-protein interaction|interact]] with
* [[Dopamine transporter]],<ref name="pmid12672538">{{cite journal | vauthors = Wersinger C, Sidhu A | title = Attenuation of dopamine transporter activity by alpha-synuclein | journal = Neuroscience Letters | volume = 340 | issue = 3 | pages = 189–92 | date = April 2003 | pmid = 12672538 | doi = 10.1016/S0304-3940(03)00097-1 }}</ref><ref name="pmid11292651">{{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 = 916–26 | date = April 2001 | pmid = 11292651 | doi = 10.1096/fj.00-0334com }}</ref>
* [[Parkin (ligase)]],<ref name="pmid11588587">{{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 = 2839–43 | date = September 2001 | pmid = 11588587 | doi = 10.1097/00001756-200109170-00017 | author10-link = Benjamin Wolozin }}</ref><ref name="pmid18195004">{{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 = 6979–87 | date = March 2008 | pmid = 18195004 | doi = 10.1074/jbc.M710418200 }}</ref>
* [[Phospholipase D1]],<ref name="pmid11821392">{{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 = 12334–42 | date = April 2002 | pmid = 11821392 | doi = 10.1074/jbc.M110414200 }}</ref>
* [[SNCAIP]],<ref name="pmid12044636">{{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 = 119–23 | date = June 2002 | pmid = 12044636 | doi = 10.1016/S0304-3940(02)00253-7 }}</ref><ref name="pmid1742726">{{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 = 6529–38 | date = December 1991 | pmid = 1742726 | doi =  }}</ref><ref name="pmid11331421">{{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 = 929–34 | date = May 2001 | pmid = 11331421 | doi = 10.1046/j.1471-4159.2001.00301.x }}</ref><ref name="pmid10319874">{{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 | author12-link=Ted M. Dawson | title = Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions | journal = Nature Genetics | volume = 22 | issue = 1 | pages = 110–4 | date = May 1999 | pmid = 10319874 | doi = 10.1038/8820 }}</ref>
* [[Tau protein]].<ref name="pmid10464279">{{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 = 25481–9 | date = September 1999 | pmid = 10464279 | doi = 10.1074/jbc.274.36.25481 }}</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 }}</ref>
* [[Beta amyloid]]<ref name=pmid22734715>{{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 = 883–90 | date = September 2012 | pmid = 22734715 | doi = 10.1111/j.1471-4159.2012.07847.x | url = https://www.ncbi.nlm.nih.gov/pubmed/?term=Cross-seeding+effects+of+amyloid+β-protein+and+α-synuclein }}</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

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

== Further reading ==
{{Refbegin|33em}}
* {{cite web | url = https://www.nytimes.com/2002/05/21/health/in-folding-proteins-clues-to-many-diseases.html | title = In Folding Proteins, Clues to Many Diseases -  | author = Blakeslee S | authorlink = | date = 2002-05-27 | work = | publisher = New York Times | pages = | quote = | access-date = }}
* {{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 | volume = 276 | issue = 5321 | pages = 2045–7 | date = June 1997 | pmid = 9197268 | doi = 10.1126/science.276.5321.2045 }}
* {{cite journal | vauthors = Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Müller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C | title = Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies | journal = The Journal of Clinical Investigation | volume = 110 | issue = 10 | pages = 1429–39 | date = November 2002 | pmid = 12438441 | pmc = 151810 | doi = 10.1172/JCI15777 }}
* {{cite journal | vauthors = George JM | title = The synucleins | journal = Genome Biology | volume = 3 | issue = 1 | pages = REVIEWS3002 | year = 2001 | pmid = 11806835 | pmc = 150459 | doi = 10.1186/gb-2001-3-1-reviews3002 }}
* {{cite journal | vauthors = Lavedan C | title = The synuclein family | journal = Genome Research | volume = 8 | issue = 9 | pages = 871–80 | date = September 1998 | pmid = 9750188 | doi = 10.1101/gr.8.9.871 }}
* {{cite journal | vauthors = Ozawa T, Wakabayashi K, Oyanagi K | title = [Recent progress in the research of multiple system atrophy with special references to alpha-synuclein and suprachiasmatic nucleus] | journal = No to Shinkei = Brain and Nerve | volume = 54 | issue = 2 | pages = 111–7 | date = February 2002 | pmid = 11889756 | doi =  }}
* {{cite journal | vauthors = Cole NB, Murphy DD | title = The cell biology of alpha-synuclein: a sticky problem? | journal = Neuromolecular Medicine | volume = 1 | issue = 2 | pages = 95–109 | year = 2002 | pmid = 12025860 | doi = 10.1385/NMM:1:2:95 }}
* {{cite journal | vauthors = Iwatsubo T | title = [alpha-synuclein and Parkinson's disease] | journal = Seikagaku. The Journal of Japanese Biochemical Society | volume = 74 | issue = 6 | pages = 477–82 | date = June 2002 | pmid = 12138709 | doi =  }}
* {{cite journal | vauthors = Trojanowski JQ, Lee VM | title = Parkinson's disease and related synucleinopathies are a new class of nervous system amyloidoses | journal = Neurotoxicology | volume = 23 | issue = 4-5 | pages = 457–60 | date = October 2002 | pmid = 12428717 | doi = 10.1016/S0161-813X(02)00065-7 }}
* {{cite journal | vauthors = Alves da Costa C | title = Recent advances on alpha-synuclein cell biology: functions and dysfunctions | journal = Current Molecular Medicine | volume = 3 | issue = 1 | pages = 17–24 | date = February 2003 | pmid = 12558071 | doi = 10.2174/1566524033361690 }}
* {{cite journal | vauthors = Ma QL, Chan P, Yoshii M, Uéda K | title = Alpha-synuclein aggregation and neurodegenerative diseases | journal = Journal of Alzheimer's Disease | volume = 5 | issue = 2 | pages = 139–48 | date = April 2003 | pmid = 12719631 | doi =  }}
* {{cite journal | vauthors = Di Rosa G, Puzzo D, Sant'Angelo A, Trinchese F, Arancio O | title = Alpha-synuclein: between synaptic function and dysfunction | journal = Histology and Histopathology | volume = 18 | issue = 4 | pages = 1257–66 | date = October 2003 | pmid = 12973692 | doi = 10.14670/HH-18.1257 }}
* {{cite journal | vauthors = Baptista MJ, Cookson MR, Miller DW | title = Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease | journal = The Neuroscientist | volume = 10 | issue = 1 | pages = 63–72 | date = February 2004 | pmid = 14987449 | doi = 10.1177/1073858403260392 }}
* {{cite journal | vauthors = Kim S, Seo JH, Suh YH | title = Alpha-synuclein, Parkinson's disease, and Alzheimer's disease | journal = Parkinsonism & Related Disorders | volume = 10 Suppl 1 | issue =  | pages = S9-13 | date = May 2004 | pmid = 15109581 | doi = 10.1016/j.parkreldis.2003.11.005 }}
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* {{cite journal | vauthors = Pankratz N, Foroud T | title = Genetics of Parkinson disease | journal = NeuroRx | volume = 1 | issue = 2 | pages = 235–42 | date = April 2004 | pmid = 15717024 | pmc = 534935 | doi = 10.1602/neurorx.1.2.235 }}
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{{Refend}}

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

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

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