Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative motor disorders, marked by chronic progressive loss of neurons in the substantia nigra. It has long been believed that PD is caused by environmental factors. The discovery of genetic factors involved in PD has improved the understanding of the pathology of the disease. The first gene found to be mutated in PD encodes for the presynaptic protein α-synuclein. α-Synuclein is a major component of Lewy bodies and Lewy neurites, which represent the morphological hallmarks of the disease. The mechanisms by which α-synuclein is involved in nigral cell death remain poorly understood. Moreover, the factors triggering the formation of α-synuclein-positive inclusion bodies remain enigmatic. Indeed, even the normal cellular functions of α-synuclein and of the other synucleins (β-synuclein and γ-synuclein) are still unknown. Several lines of evidence suggest that they play a role in the regulation of vesicular turnover under normal nonpathological conditions.
Similar content being viewed by others
References
Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252
Alimova-Kost MV, Ninkina NN, Imreh S, Gnuchev NV, Adu J, Davies AM, Buchman VL (1999) Genomic structure and chromosomal localization of the mouse persyn gene. Genomics 56:224–227
Andringa G, Du F, Chase TN, Bennett MC (2003) Mapping of rat brain using the synuclein-1 monoclonal antibody reveals somatodendritic expression of alphasynuclein in populations of neurons homologous to those vulnerable to Lewy body formation in human synucleopathies. J Neuropathol Exp Neurol 62:1060–1075
Auluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8:1185–1186
Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555
Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. Bioessays 24:308–318
Bradbury J (2003) Alpha-synuclein gene triplication discovered in Parkinson’s disease. Lancet Neurol 2:715
Brenz Verca MS, Bahi A, Boyer F, Wagner GC, Dreyer JL (2003) Distribution of alpha- and gamma-synucleins in the adult rat brain and their modification by highdose cocaine treatment. Eur J Neurosci 18:1923–1938
Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823:1–10
Buchman VL, Adu J, Pinon LG, Ninkina NN, Davies AM (1998a) Persyn, a member of the synuclein family, influences neurofilament network integrity. Nat Neurosci 1:101–103
Buchman VL, Hunter HJ, Pinon LG, Thompson J, Privalova EM, Ninkina NN, Davies AM (1998b) Persyn, a member of the synuclein family, has a distinct pattern of expression in the developing nervous system. J Neurosci 18:9335–9341
Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22:8797–8807
Chen PE, Specht CG, Morris RG, Schoepfer R (2002) Spatial learning is unimpaired in mice containing a deletion of the alpha-synuclein locus. Eur J Neurosci 16:154–158
Chen X, Silva HA de, Pettenati MJ, Rao PN, George-Hyslop P, Roses AD, Xia Y, Horsburgh K, Ueda K, Saitoh T (1995) The human NACP/alpha-synuclein gene: chromosome assignment to 4q21.3–q22 and TaqI RFLP analysis. Genomics 26:425–427
Chung KK, Dawson VL, Dawson TM (2001a) The role of the ubiquitin-proteasomal pathway in Parkinson’s disease and other neurodegenerative disorders. Trend Neurosci 24:7–14
Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001b) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144–1150
Ciechanover A (2001) Linking ubiquitin, parkin and synphilin-1. Nat Med 7:1108–1109
Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–1320
Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R (2002) Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 99:14524–14529
Davidson WS, Jonas A, Clayton DF, George JM (1998) Stabilization of alphasynuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443–9449
Eliezer D, Kutluay E, Bussell R Jr, Browne G (2001) Conformational properties of alpha-synuclein in its free and lipid-associated states. J Mol Biol 307:1061–1073
Ellis CE, Schwartzberg PL, Grider TL, Fink DW, Nussbaum RL (2001) Alphasynuclein is phosphorylated by members of the Src family of protein-tyrosine kinases. J Biol Chem 276:3879–3884
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 (1999) Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22:110–114
Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M, Maraganore D, Gwinn-Hardy K, Wszolek Z, Dickson D, Langston JW (2004) Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55:174–179
Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398
Flowers JM, Leigh PN, Davies AM, Ninkina NN, Buchman VL, Vaughan J, Wood NW, Powell JF (1999) Mutations in the gene encoding human persyn are not associated with amyotrophic lateral sclerosis or familial Parkinson’s disease. Neurosci Lett 274:21–24
Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164
Galvin JE, Schuck TM, Lee VM, Trojanowski JQ (2001) Differential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigra. Exp Neurol 168:347–355
George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–372
Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989
Giasson BI, Duda JE, Forman MS, Lee VM, Trojanowski JQ (2001) Prominent perikaryal expression of alpha- and beta-synuclein in neurons of dorsal root ganglion and in medullary neurons. Exp Neurol 172:354–362
Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533
Gibb WR, Scott T, Lees AJ (1991) Neuronal inclusions of Parkinson’s disease. Mov Disord 6:2–11
Gispert S, Turco DD, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, Korf HW, Deller T, Braak H, Auburger G, Nussbaum RL (2003) Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol Cell Neurosci 24:419–429
Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501
Goldberg MS, Lansbury PT Jr (2000) Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson’s disease? Nat Cell Biol 2:E115–E119
Hartman VN, Miller MA, Clayton DF, Liu WC, Kroodsma DE, Brenowitz EA (2001) Testosterone regulates alpha-synuclein mRNA in the avian song system. Neuroreport 12:943–946
Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, Lee VM, Trojanowski JQ, Mann D, Iwatsubo T (2002) Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem 277:49071–49076
Hashimoto M, Takenouchi T, Rockenstein E, Masliah E (2003) Alpha-synuclein upregulates expression of caveolin-1 and down-regulates extracellular signal regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson’s disease. J Neurochem 85:1468–1479
Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479
Hong L, Ko HW, Gwag BJ, Joe E, Lee S, Kim YT, Suh YH (1998) The cDNA cloning and ontogeny of mouse alpha-synuclein. Neuroreport 9:1239–1243
Impey S, Obrietan K, Storm DR (1999) Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23:11–14
Ischiropoulos H (2003) Oxidative modifications of alpha-synuclein. Ann NY Acad Sci 991:93–100
Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, Silva HA de, Kittel A, Saitoh T (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475
Iwatsubo T (2003) Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 250:III11–III14
Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345:27–32
Jakowec MW, Donaldson DM, Barba J, Petzinger GM (2001) Postnatal expression of alpha-synuclein protein in the rodent substantia nigra and striatum. Dev Neurosci 23:91–99
Jenco JM, Rawlingson A, Daniels B, Morris AJ (1998) Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. Biochemistry 37:4901–4909
Jensen PH, Hojrup P, Hager H, Nielsen MS, Jacobsen L, Olesen OF, Gliemann J, Jakes R (1997) Binding of Abeta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC. Biochem J 323:539–546
Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G, Joseph BK, Rosen C, Shi YE (1997) Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 57:759–764
Jin H, Clayton DF (1997) Synelfin regulation during the critical period for song learning in normal and isolated juvenile zebra finches. Neurobiol Learn Mem 68:271–284
Junn E, Mouradian MM (2002) Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett 320:146–150
Kawamata H, McLean PJ, Sharma N, Hyman BT (2001) Interaction of alphasynuclein and synphilin-1: effect of Parkinson’s disease-associated mutations. J Neurochem 77:929–934
Kim TD, Paik SR, Yang CH (2002) Structural and functional implications of C-terminal regions of alpha-synuclein. Biochemistry 41:13782–13790
Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Björklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791
Klein RL, King MA, Hamby ME, Meyer EM (2002) Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther 13:605–612
Kobayashi H, Kruger R, Markopoulou K, Wszolek Z, Chase B, Taka H, Mineki R, Murayama K, Riess O, Mizuno Y, Hattori N (2003) Haploinsufficiency at the alphasynuclein gene underlies phenotypic severity in familial Parkinson’s disease. Brain 126:32–42
Kowall NW, Hantraye P, Brouillet E, Beal MF, McKee AC, Ferrante RJ (2000) MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons. Neuroreport 11:211–213
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108
Kuhn K, Wellen J, Link N, Maskri L, Lubbert H, Stichel CC (2003) The mouse MPTP model: gene expression changes in dopaminergic neurons. Eur J Neurosci 17:1–12
Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of alpha-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253
Lakso M, Vartiainen S, Moilanen AM, Sirvio J, Thomas JH, Nass R, Blakely RD, Wong G (2003) Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem 86:165–172
Larsen CN, Krantz BA, Wilkinson KD (1998) Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry 37:3358–3368
Lavedan C (1998) The synuclein family. Genome Res 8:871–880
Lavedan C, Buchholtz S, Auburger G, Albin RL, Athanassiadou A, Blancato J, Burguera JA, Ferrell RE, Kostic V, Leroy E, Leube B, Mota-Vieira L, Papapetropoulos T, Pericak-Vance MA, Pinkus J, Scott WK, Ulm G, Vasconcelos J, Vilchez JJ, Nussbaum RL, Polymeropoulos MH (1998a) Absence of mutation in the beta- and gamma-synuclein genes in familial autosomal dominant Parkinson’s disease. DNA Res 5:401–402
Lavedan C, Leroy E, Dehejia A, Buchholtz S, Dutra A, Nussbaum RL, Polymeropoulos MH (1998b) Identification, localization and characterization of the human gamma-synuclein gene. Hum Genet 103:106–112
Lee FJ, Liu F, Pristupa ZB, Niznik HB (2001) Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. Fed Am Soc Exp Biol J 15:916–926
Lee G, Tanaka M, Park K, Lee SS, Kim YM, Junn E, Lee SH, Mouradian MM (2004) Casein kinase II-mediated phosphorylation regulates alpha-synuclein/synphilin-1 interaction and inclusion body formation. J Biol Chem 279:6834–6839
Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53→Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968–8973
Li J, Uversky VN, Fink AL (2002a) Conformational behavior of human alphasynuclein is modulated by familial Parkinson’s disease point mutations A30P and A53T. Neurotoxicology 23:553–567
Li JY, Henning JP, Dahlstrom A (2002b) Differential localization of alpha-, beta- and gamma-synucleins in the rat CNS. Neuroscience 113:463–478
Li W, Hoffman PN, Stirling W, Price DL, Lee MK (2004) Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson’s disease-linked mutations. J Neurochem 88:401–410
Lincoln S, Crook R, Chartier-Harlin MC, Gwinn-Hardy K, Baker M, Mouroux V, Richard F, Becquet E, Amouyel P, Destee A, Hardy J, Farrer M (1999a) No pathogenic mutations in the beta-synuclein gene in Parkinson’s disease. Neurosci Lett 269:107–109
Lincoln S, Gwinn-Hardy K, Goudreau J, Chartier-Harlin MC, Baker M, Mouroux V, Richard F, Destee A, Becquet E, Amouyel P, Lynch T, Hardy J, Farrer M (1999b) No pathogenic mutations in the persyn gene in Parkinson’s disease. Neurosci Lett 259:65–66
Lo BC, Ridet JL, Schneider BL, Deglon N, Aebischer P (2002) Alpha-synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci USA 99:10813–10818
Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942
Maroteaux L, Scheller RH (1991) The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Brain Res Mol Brain Res 11:335–343
Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815
Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269
Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250
Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte DA (2001) Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 8:535–539
McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119–127
McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shashidharan P, Jennert P, Olanow CW (2002) Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81:301–306
Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K (2002) Immunohistochemical comparison of alpha- and beta-synuclein in adult rat central nervous system. Brain Res 941:118–126
Murphy DD, Rueter SM, Trojanowski JQ, Lee VM (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20:3214–3220
Murray IV, Giasson BI, Quinn SM, Koppaka V, Axelsen PH, Ischiropoulos H, Trojanowski JQ, Lee VM (2003) Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42:8530–8540
Nakajo S, Tsukada K, Omata K, Nakamura Y, Nakaya K (1993) A new brain-specific 14-kDa protein is a phosphoprotein. Its complete amino acid sequence and evidence for phosphorylation. Eur J Biochem 217:1057–1063
Nakajo S, Shioda S, Nakai Y, Nakaya K (1994) Localization of phosphoneuroprotein 14 (PNP 14) and its mRNA expression in rat brain determined by immunocytochemistry and in situ hybridization. Brain Res Mol Brain Res 27:81–86
Nakamura T, Yamashita H, Takahashi T, Nakamura S (2001) Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. Biochem Biophys Res Commun 280:1085–1092
Nakamura T, Yamashita H, Nagano Y, Takahashi T, Avraham S, Avraham H, Matsumoto M, Nakamura S (2002) Activation of Pyk2/RAFTK induces tyrosine phosphorylation of alpha-synuclein via Src-family kinases. FEBS Lett 521:190–194
Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Muller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C (2002) Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alphasynucleinopathies. J Clin Invest 110:1429–1439
Ninkina NN, Alimova-Kost MV, Paterson JW, Delaney L, Cohen BB, Imreh S, Gnuchev NV, Davies AM, Buchman VL (1998) Organization, expression and polymorphism of the human persyn gene. Hum Mol Genet 7:1417–1424
Ninkina N, Papachroni K, Robertson DC, Schmidt O, Delaney L, O’Neill F, Court F, Rosenthal A, Fleetwood-Walker SM, Davies AM, Buchman VL (2003) Neurons expressing the highest levels of gamma-synuclein are unaffected by targeted inactivation of the gene. Mol Cell Biol 23:8233–8245
Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T, Meijer L, Kahle PJ, Haass C (2000) Constitutive phosphorylation of the Parkinson’s disease associated alpha-synuclein. J Biol Chem 275:390–397
Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B (1999) Alpha-synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19:5782–5791
Park JY, Lansbury PT Jr (2003) Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson’s disease. Biochemistry 42:3696–3700
Park SM, Jung HY, Kim TD, Park JH, Yang CH, Kim J (2002) Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of alpha-synuclein, a molecular chaperone. J Biol Chem 277:28512–28520
Pendleton RG, Parvez F, Sayed M, Hillman R (2002) Effects of pharmacological agents upon a transgenic model of Parkinson’s disease in Drosophila melanogaster. J Pharmacol Exp Ther 300:91–96
Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22:3090–3099
Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC (1996) Mapping of a gene for Parkinson’s disease to chromosome 4q21–q23. Science 274:1197–1199
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 (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047
Pronin AN, Morris AJ, Surguchov A, Benovic JL (2000) Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J Biol Chem 275:26515–26522
Putten H van der, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human alphasynuclein. J Neurosci 20:6021–6029
Rathke-Hartlieb S, Kahle PJ, Neumann M, Ozmen L, Haid S, Okochi M, Haass C, Schulz JB (2001) Sensitivity to MPTP is not increased in Parkinson’s disease associated mutant alpha-synuclein transgenic mice. J Neurochem 77:1181–1184
Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ (2002) Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol 175:35–48
Rochet JC, Lansbury PT Jr (2000) Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 10:60–68
Rochet JC, Conway KA, Lansbury PT Jr (2000) Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse alphasynuclein. Biochemistry 39:10619–10626
Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated alpha-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654
Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM (2003) Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies. Am J Pathol 163:91–100
Sawada H, Kohno R, Kihara T, Izumi Y, Sakka N, Ibi M, Nakanishi M, Nakamizo T, Yamakawa K, Shibasaki H, Yamamoto N, Akaike A, Inden M, Kitamura Y, Taniguchi T, Shimohama S (2003) Proteasome mediates dopaminergic neuronal degeneration and its inhibition causes alpha-synuclein inclusions. J Biol Chem 279:10710–10719
Schluter OM, Fornai F, Alessandri MG, Takamori S, Geppert M, Jahn R, Sudhof TC (2003) Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinsonism in mice. Neuroscience 118:985–1002
Sharma N, McLean PJ, Kawamata H, Irizarry MC, Hyman BT (2001) Alpha-synuclein has an altered conformation and shows a tight intermolecular interaction with ubiquitin in Lewy bodies. Acta Neuropathol (Berl) 102:329–334
Shibasaki Y, Baillie DA, St Clair D, Brookes AJ (1995) High-resolution mapping of SNCA encoding alpha-synuclein, the non-A beta component of Alzheimer’s disease amyloid precursor, to human chromosome 4q21.3→q22 by fluorescence in situ hybridization. Cytogenet Cell Genet 71:54–55
Shibayama-Imazu T, Okahashi I, Omata K, Nakajo S, Ochiai H, Nakai Y, Hama T, Nakamura Y, Nakaya K (1993) Cell and tissue distribution and developmental change of neuron specific 14 kDa protein (phosphoneuroprotein 14). Brain Res 622:17–25
Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of alphasynuclein by parkin from human brain: implications for Parkinson’s disease. Science 293:263–269
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 (2003) Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302:841
Singleton A, Gwinn-Hardy K, Sharabi Y, Li ST, Holmes C, Dendi R, Hardy J, Singleton A, Crawley A, Goldstein DS (2004) Association between cardiac denervation and parkinsonism caused by {alpha}-synuclein gene triplication. Brain 127:768–772
Song DD, Shults CW, Sisk A, Rockenstein E, Masliah E (2004) Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol 186:158–172
Sopher BL, Koszdin KL, McClain ME, Myrick SB, Martinez RA, Smith AC, La Spada AR (2001) Genomic organization, chromosome location, and expression analysis of mouse beta-synuclein, a candidate for involvement in neurodegeneration. Cytogenet Cell Genet 93:117–123
Specht CG, Schoepfer R (2001) Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci 2:11
Spillantini MG, Divane A, Goedert M (1995) Assignment of human alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes 4q21 and 5q35. Genomics 27:379–381
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473
Subramaniam S, Strelau J, Unsicker K (2003) Growth differentiation factor-15 prevents low potassium-induced cell death of cerebellar granule neurons by differential regulation of Akt and ERK pathways. J Biol Chem 278:8904–8912
Surguchov A, Surgucheva I, Solessio E, Baehr W (1999) Synoretin—a new protein belonging to the synuclein family. Mol Cell Neurosci 13:95–103
Surguchov A, Palazzo RE, Surgucheva I (2001) Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction. Cell Motil Cytoskeleton 49:218–228
Takahashi H, Wakabayashi K (2001) The cellular pathology of Parkinson’s disease. Neuropathology 21:315–322
Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM (2004) Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279:4625–4631
Tiunova AA, Anokhin KV, Saha AR, Schmidt O, Hanger DP, Anderton BH, Davies AM, Ninkina NN, Buchman VL (2000) Chicken synucleins: cloning and expression in the developing embryo. Mech Dev 99:195–198
Tobe T, Nakajo S, Tanaka A, Mitoya A, Omata K, Nakaya K, Tomita M, Nakamura Y (1992) Cloning and characterization of the cDNA encoding a novel brain-specific 14-kDa protein. J Neurochem 59:1624–1629
Tompkins MM, Hill WD (1997) Contribution of somal Lewy bodies to neuronal death. Brain Res 775:24–29
Touchman JW, Dehejia A, Chiba-Falek O, Cabin DE, Schwartz JR, Orrison BM, Polymeropoulos MH, Nussbaum RL (2001) Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element. Genome Res 11:78–86
Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286
Uversky VN (2003) A protein-chameleon: conformational plasticity of alpha- synuclein, a disordered protein involved in neurodegenerative disorders. J Biomol Struct Dyn 21:211–234
Uversky VN, Li J, Fink AL (2001) Pesticides directly accelerate the rate of alphasynuclein fibril formation: a possible factor in Parkinson’s disease. FEBS Lett 500:105–108
Uversky VN, Li J, Souillac P, Millett IS, Doniach S, Jakes R, Goedert M, Fink AL (2002) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem 277:11970–11978
Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M, Takahashi H (1998) Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol (Berl) 96:445–452
Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35:13709–13715
Windisch M, Hutter-Paier B, Rockenstein E, Hashimoto M, Mallory M, Masliah E (2002) Development of a new treatment for Alzheimer’s disease and Parkinson’s disease using anti-aggregatory beta-synuclein-derived peptides. J Mol Neurosci 19:63–69
Withers GS, George JM, Banker GA, Clayton DF (1997) Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res Dev Brain Res 99:87–94
Xia Y, Saitoh T, Ueda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (2001) Characterization of the human alpha-synuclein gene: genomic structure, transcription start site, promoter region and polymorphisms. J Alzheimers Dis 3:485–494
Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA (2002) Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8:600–606
Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Tortosa EG, Del Ser T, Munoz DG, De Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173
Zhou W, Schaack J, Zawada WM, Freed CR (2002) Overexpression of human alphasynuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Res 926:42–50
Author information
Authors and Affiliations
Corresponding author
Additional information
The work of O. von Bohlen und Halbach is supported by the DFG (Forschergruppe FOR 302 and SFB 636)
Rights and permissions
About this article
Cite this article
von Bohlen und Halbach, O. Synucleins and their relationship to Parkinson’s disease. Cell Tissue Res 318, 163–174 (2004). https://doi.org/10.1007/s00441-004-0921-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-004-0921-7