Cell and Tissue Research

, Volume 318, Issue 1, pp 163–174 | Cite as

Synucleins and their relationship to Parkinson’s disease



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.


Parkinson’s disease Synuclein (α, β and γ) Lewy bodies Substantia nigra Dopamine Human Rodent Song bird 


  1. 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 25:239–252CrossRefPubMedGoogle Scholar
  2. 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 56:224–227CrossRefPubMedGoogle Scholar
  3. 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 62:1060–1075PubMedGoogle Scholar
  4. Auluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8:1185–1186CrossRefPubMedGoogle Scholar
  5. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555CrossRefPubMedGoogle Scholar
  6. Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. Bioessays 24:308–318CrossRefPubMedGoogle Scholar
  7. Bradbury J (2003) Alpha-synuclein gene triplication discovered in Parkinson’s disease. Lancet Neurol 2:715CrossRefGoogle Scholar
  8. 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 18:1923–1938CrossRefPubMedGoogle Scholar
  9. Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823:1–10CrossRefPubMedGoogle Scholar
  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 1:101–103CrossRefPubMedGoogle Scholar
  11. 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 18:9335–9341PubMedGoogle Scholar
  12. 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 22:8797–8807PubMedGoogle Scholar
  13. 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 16:154–158CrossRefPubMedGoogle Scholar
  14. 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 26:425–427CrossRefPubMedGoogle Scholar
  15. Chung KK, Dawson VL, Dawson TM (2001a) The role of the ubiquitin-proteasomal pathway in Parkinson’s disease and other neurodegenerative disorders. Trend Neurosci 24:7–14CrossRefPubMedGoogle Scholar
  16. 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 7:1144–1150CrossRefPubMedGoogle Scholar
  17. Ciechanover A (2001) Linking ubiquitin, parkin and synphilin-1. Nat Med 7:1108–1109CrossRefPubMedGoogle Scholar
  18. 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 4:1318–1320CrossRefPubMedGoogle Scholar
  19. 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 99:14524–14529CrossRefPubMedGoogle Scholar
  20. Davidson WS, Jonas A, Clayton DF, George JM (1998) Stabilization of alphasynuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443–9449CrossRefPubMedGoogle Scholar
  21. 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 307:1061–1073CrossRefPubMedGoogle Scholar
  22. 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 276:3879–3884CrossRefPubMedGoogle Scholar
  23. 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 22:110–114CrossRefPubMedGoogle Scholar
  24. 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 55:174–179CrossRefPubMedGoogle Scholar
  25. Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398CrossRefPubMedGoogle Scholar
  26. 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 274:21–24CrossRefPubMedGoogle Scholar
  27. 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 4:160–164CrossRefPubMedGoogle Scholar
  28. 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 168:347–355CrossRefPubMedGoogle Scholar
  29. 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 15:361–372CrossRefPubMedGoogle Scholar
  30. 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 290:985–989CrossRefPubMedGoogle Scholar
  31. 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 172:354–362CrossRefPubMedGoogle Scholar
  32. 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 34:521–533CrossRefPubMedGoogle Scholar
  33. Gibb WR, Scott T, Lees AJ (1991) Neuronal inclusions of Parkinson’s disease. Mov Disord 6:2–11PubMedGoogle Scholar
  34. 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 24:419–429CrossRefPubMedGoogle Scholar
  35. Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501CrossRefPubMedGoogle Scholar
  36. 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–E119CrossRefPubMedGoogle Scholar
  37. Hartman VN, Miller MA, Clayton DF, Liu WC, Kroodsma DE, Brenowitz EA (2001) Testosterone regulates alpha-synuclein mRNA in the avian song system. Neuroreport 12:943–946CrossRefPubMedGoogle Scholar
  38. 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 277:49071–49076CrossRefPubMedGoogle Scholar
  39. 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 85:1468–1479CrossRefPubMedGoogle Scholar
  40. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479CrossRefPubMedGoogle Scholar
  41. 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 9:1239–1243PubMedGoogle Scholar
  42. Impey S, Obrietan K, Storm DR (1999) Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23:11–14CrossRefPubMedGoogle Scholar
  43. Ischiropoulos H (2003) Oxidative modifications of alpha-synuclein. Ann NY Acad Sci 991:93–100PubMedGoogle Scholar
  44. 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 14:467–475PubMedGoogle Scholar
  45. Iwatsubo T (2003) Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 250:III11–III14CrossRefPubMedGoogle Scholar
  46. Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345:27–32CrossRefPubMedGoogle Scholar
  47. Jakowec MW, Donaldson DM, Barba J, Petzinger GM (2001) Postnatal expression of alpha-synuclein protein in the rodent substantia nigra and striatum. Dev Neurosci 23:91–99CrossRefPubMedGoogle Scholar
  48. 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 37:4901–4909CrossRefPubMedGoogle Scholar
  49. 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 323:539–546PubMedGoogle Scholar
  50. 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 57:759–764PubMedGoogle Scholar
  51. Jin H, Clayton DF (1997) Synelfin regulation during the critical period for song learning in normal and isolated juvenile zebra finches. Neurobiol Learn Mem 68:271–284CrossRefPubMedGoogle Scholar
  52. Junn E, Mouradian MM (2002) Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett 320:146–150CrossRefPubMedGoogle Scholar
  53. Kawamata H, McLean PJ, Sharma N, Hyman BT (2001) Interaction of alphasynuclein and synphilin-1: effect of Parkinson’s disease-associated mutations. J Neurochem 77:929–934CrossRefPubMedGoogle Scholar
  54. Kim TD, Paik SR, Yang CH (2002) Structural and functional implications of C-terminal regions of alpha-synuclein. Biochemistry 41:13782–13790CrossRefPubMedGoogle Scholar
  55. 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 22:2780–2791PubMedGoogle Scholar
  56. 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 13:605–612CrossRefPubMedGoogle Scholar
  57. 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 126:32–42CrossRefPubMedGoogle Scholar
  58. 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 11:211–213PubMedGoogle Scholar
  59. 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 18:106–108PubMedGoogle Scholar
  60. 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 17:1–12CrossRefPubMedGoogle Scholar
  61. Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of alpha-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253PubMedGoogle Scholar
  62. 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 86:165–172CrossRefPubMedGoogle Scholar
  63. Larsen CN, Krantz BA, Wilkinson KD (1998) Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry 37:3358–3368CrossRefPubMedGoogle Scholar
  64. Lavedan C (1998) The synuclein family. Genome Res 8:871–880PubMedGoogle Scholar
  65. 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 5:401–402PubMedGoogle Scholar
  66. 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 103:106–112CrossRefPubMedGoogle Scholar
  67. 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 15:916–926CrossRefGoogle Scholar
  68. 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 279:6834–6839CrossRefPubMedGoogle Scholar
  69. 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 99:8968–8973CrossRefPubMedGoogle Scholar
  70. 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 23:553–567CrossRefPubMedGoogle Scholar
  71. Li JY, Henning JP, Dahlstrom A (2002b) Differential localization of alpha-, beta- and gamma-synucleins in the rat CNS. Neuroscience 113:463–478CrossRefPubMedGoogle Scholar
  72. 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 88:401–410PubMedGoogle Scholar
  73. 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 269:107–109CrossRefPubMedGoogle Scholar
  74. 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 259:65–66CrossRefPubMedGoogle Scholar
  75. 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 99:10813–10818CrossRefPubMedGoogle Scholar
  76. Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942CrossRefPubMedGoogle Scholar
  77. Maroteaux L, Scheller RH (1991) The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Brain Res Mol Brain Res 11:335–343CrossRefPubMedGoogle Scholar
  78. Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815PubMedGoogle Scholar
  79. 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 287:1265–1269CrossRefPubMedGoogle Scholar
  80. 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 98:12245–12250CrossRefPubMedGoogle Scholar
  81. 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 8:535–539CrossRefPubMedGoogle Scholar
  82. 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 10:119–127CrossRefPubMedGoogle Scholar
  83. 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 81:301–306CrossRefPubMedGoogle Scholar
  84. 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 941:118–126CrossRefPubMedGoogle Scholar
  85. 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 20:3214–3220PubMedGoogle Scholar
  86. 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 42:8530–8540CrossRefPubMedGoogle Scholar
  87. 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 217:1057–1063PubMedGoogle Scholar
  88. 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 27:81–86CrossRefPubMedGoogle Scholar
  89. Nakamura T, Yamashita H, Takahashi T, Nakamura S (2001) Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. Biochem Biophys Res Commun 280:1085–1092CrossRefPubMedGoogle Scholar
  90. 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 521:190–194CrossRefPubMedGoogle Scholar
  91. 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 110:1429–1439CrossRefPubMedGoogle Scholar
  92. 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 7:1417–1424CrossRefPubMedGoogle Scholar
  93. 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 23:8233–8245CrossRefPubMedGoogle Scholar
  94. 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 275:390–397CrossRefPubMedGoogle Scholar
  95. 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 19:5782–5791PubMedGoogle Scholar
  96. Park JY, Lansbury PT Jr (2003) Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson’s disease. Biochemistry 42:3696–3700CrossRefPubMedGoogle Scholar
  97. 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 277:28512–28520CrossRefPubMedGoogle Scholar
  98. 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 300:91–96CrossRefPubMedGoogle Scholar
  99. 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 22:3090–3099PubMedGoogle Scholar
  100. 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 274:1197–1199CrossRefPubMedGoogle Scholar
  101. 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 276:2045–2047CrossRefPubMedGoogle Scholar
  102. 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 275:26515–26522CrossRefPubMedGoogle Scholar
  103. 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 20:6021–6029PubMedGoogle Scholar
  104. 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 77:1181–1184CrossRefPubMedGoogle Scholar
  105. 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 175:35–48CrossRefPubMedGoogle Scholar
  106. Rochet JC, Lansbury PT Jr (2000) Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 10:60–68CrossRefPubMedGoogle Scholar
  107. Rochet JC, Conway KA, Lansbury PT Jr (2000) Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse alphasynuclein. Biochemistry 39:10619–10626CrossRefPubMedGoogle Scholar
  108. 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 62:644–654PubMedGoogle Scholar
  109. 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 163:91–100PubMedGoogle Scholar
  110. 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 279:10710–10719CrossRefPubMedGoogle Scholar
  111. 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 118:985–1002CrossRefPubMedGoogle Scholar
  112. 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) 102:329–334Google Scholar
  113. 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 71:54–55PubMedGoogle Scholar
  114. 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 622:17–25CrossRefPubMedGoogle Scholar
  115. 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 293:263–269CrossRefPubMedGoogle Scholar
  116. 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 302:841CrossRefPubMedGoogle Scholar
  117. 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 127:768–772CrossRefPubMedGoogle Scholar
  118. 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 186:158–172CrossRefPubMedGoogle Scholar
  119. 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 93:117–123CrossRefPubMedGoogle Scholar
  120. Specht CG, Schoepfer R (2001) Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci 2:11CrossRefPubMedGoogle Scholar
  121. Spillantini MG, Divane A, Goedert M (1995) Assignment of human alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes 4q21 and 5q35. Genomics 27:379–381CrossRefPubMedGoogle Scholar
  122. 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 95:6469–6473CrossRefPubMedGoogle Scholar
  123. 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 278:8904–8912CrossRefPubMedGoogle Scholar
  124. Surguchov A, Surgucheva I, Solessio E, Baehr W (1999) Synoretin—a new protein belonging to the synuclein family. Mol Cell Neurosci 13:95–103CrossRefPubMedGoogle Scholar
  125. 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 49:218–228CrossRefPubMedGoogle Scholar
  126. Takahashi H, Wakabayashi K (2001) The cellular pathology of Parkinson’s disease. Neuropathology 21:315–322CrossRefPubMedGoogle Scholar
  127. 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 279:4625–4631CrossRefPubMedGoogle Scholar
  128. 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 99:195–198CrossRefPubMedGoogle Scholar
  129. 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 59:1624–1629PubMedGoogle Scholar
  130. Tompkins MM, Hill WD (1997) Contribution of somal Lewy bodies to neuronal death. Brain Res 775:24–29CrossRefPubMedGoogle Scholar
  131. 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 11:78–86CrossRefPubMedGoogle Scholar
  132. 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 90:11282–11286PubMedGoogle Scholar
  133. Uversky VN (2003) A protein-chameleon: conformational plasticity of alpha- synuclein, a disordered protein involved in neurodegenerative disorders. J Biomol Struct Dyn 21:211–234PubMedGoogle Scholar
  134. 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 500:105–108CrossRefPubMedGoogle Scholar
  135. 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 277:11970–11978CrossRefPubMedGoogle Scholar
  136. 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) 96:445–452CrossRefGoogle Scholar
  137. 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 35:13709–13715CrossRefPubMedGoogle Scholar
  138. 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 19:63–69PubMedGoogle Scholar
  139. 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 99:87–94CrossRefPubMedGoogle Scholar
  140. 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 3:485–494CrossRefPubMedGoogle Scholar
  141. 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 8:600–606CrossRefPubMedGoogle Scholar
  142. 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 55:164–173CrossRefPubMedGoogle Scholar
  143. Zhou W, Schaack J, Zawada WM, Freed CR (2002) Overexpression of human alphasynuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Res 926:42–50CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Interdisciplinary Center for Neurosciences (IZN), Department of NeuroanatomyUniversity of HeidelbergHeidelbergGermany

Personalised recommendations