Editing Alpha-synuclein (section)

== 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 | pages = 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 | pages = 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 | pages = 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 | pages = 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 | pages = 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 | pages = 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. 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.