synuclein in familial and sporadic Lewy body disease. J Biol Chem 281: 29739–29752. 3. Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG (2003) Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 278: 44405–44411. 4. 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. 5. Singleton AB (2005) Altered alpha-synuclein homeostasis causing Parkinson’s disease: the potential roles of dardarin. Trends Neurosci 28: 416–421. 6. Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, et al. (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet 364: 1169–1171. 7. Singleton A, Gwinn-Hardy K (2004) Parkinson’s disease and dementia with Lewy bodies: a difference in dose? Lancet 364: 1105–1107. 8. Miller DW, Hague SM, Clarimon J, Baptista M, Gwinn-Hardy K, et al. (2004) Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62: 1835–1838. 9. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, et al. (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34: 521–533. 10. van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, et al. (2000) Neuropathology in mice expressing human alpha-synuclein. J Neurosci 20: 6021–6029. 11. Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404: 394–398. 12. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, et al. (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287: 1265–1269. 13. Lee MK, Stirling W, Xu Y, Xu X, Qui D, et al. (2002) Human alpha-synuclein- harboring familial Parkinson’s disease-linked Ala-53 R Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99: 8968–8973. 14. Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, et al. (2002) Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleino- pathies. J Clin Invest 110: 1429–1439. 15. Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, et al. (2006) Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26: 41–50. 16. Tofaris GK, Spillantini MG (2005) Alpha-synuclein dysfunction in Lewy body diseases. Mov Disord 20 Suppl 12: S37–44. 17. Corti O, Brice A (2007) Of Parkin and Parkinson’s: light and dark sides of a multifaceted E3 ubiquitin-protein ligase. Drug Discovery Today: Disease Mechanisms 4: 121–127. 18. Klein C, Lohmann K (2008) Parkinson disease(s). Is ‘‘Parkin disease’’ a distinct clinical entity? Neurology. 19. Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, et al. (2003) How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 54: 176–185. 20. Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, et al. (2005) Alpha- synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion forma- tion in SH-SY5Y cells. J Neurosci 25: 5544–5552. 21. Henn IH, Bouman L, Schlehe JS, Schlierf A, Schramm JE, et al. (2007) Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor- kappaB signaling. J Neurosci 27: 1868–1878. 22. Fallon L, Belanger CM, Corera AT, Kontogiannea M, Regan-Klapisz E, et al. (2006) A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol 8: 834–842. 23. Joch M, Ase AR, Chen CX, MacDonald PA, Kontogiannea M, et al. (2007) Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Mol Biol Cell 18: 3105–3118. 24. Lim KL, Chew KC, Tan JM, Wang C, Chung KK, et al. (2005) Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implica- tions for Lewy body formation. J Neurosci 25: 2002–2009. 25. Matsuda N, Kitami T, Suzuki T, Mizuno Y, Hattori N, et al. (2006) Diverse effects of pathogenic mutations of Parkin that catalyze multiple monoubiquityla- tion in vitro. J Biol Chem 281: 3204–3209. 26. Hampe C, Ardila-Osorio H, Fournier M, Brice A, Corti O (2006) Biochemical analysis of Parkinson’s disease-causing variants of Parkin, an E3 ubiquitin- protein ligase with monoubiquitylation capacity. Hum Mol Genet. 27. Pawlyk AC, Giasson BI, Sampathu DM, Perez FA, Lim KL, et al. (2003) Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age. J Biol Chem 278: 48120–48128. 28. LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11: 1214–1221. 29. Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, et al. (2004) S- nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 304: 1328–1331. PARK2 Modifies Synucleinopathy 30. Cookson MR, Hardy J, Lewis PA (2008) Genetic neuropathology of Parkinson’s disease. Int J Clin Exp Pathol 1: 217–231. 31. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, et al. (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7: 1144–1150. 32. Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37: 911–924. 33. Haywood AF, Staveley BE (2004) parkin counteracts symptoms in a Drosophila model of Parkinson’s disease. BMC Neurosci 5: 14. 34. Petrucelli L, O’Farrell C, Lockhart PJ, Baptista M, Kehoe K, et al. (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36: 1007–1019. 35. Lo Bianco C, Schneider BL, Bauer M, Sajadi A, Brice A, et al. (2004) Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha- synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci USA 101: 17510–17515. 36. Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, et al. (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12: 2277–2291. 37. Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, et al. (2000) Subcellular localization of wild-type and Parkinson’s disease-associated mutant alpha -synuclein in human and transgenic mouse brain. J Neurosci 20: 6365–6373. 38. Barneoud P, Lolivier J, Sanger DJ, Scatton B, Moser P (1997) Quantitative motor assessment in FALS mice: a longitudinal study. Neuroreport 8: 2861–2865. 39. Freichel C, Neumann M, Ballard T, Muller V, Woolley M, et al. (2007) Age- dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice. Neurobiol Aging 28: 1421–1435. 40. Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotox- icity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8: 657–663. 41. Gorbatyuk OS, Li S, Sullivan LF, Chen W, Kondrikova G, et al. (2008) The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc Natl Acad Sci U S A 105: 763–768. 42. Paleologou KE, Schmid AW, Rospigliosi CC, Kim HY, Lamberto GR, et al. (2008) Phosphorylation at S129, but not the phosphomimics S129E/D inhibits the fibrilization of alpha -synuclein. J Biol Chem. 43. Sugeno N, Takeda A, Hasegawa T, Kobayashi M, Kikuchi A, et al. (2008) Serine 129 phosphorylation of alpha-synuclein induces unfolded protein response-mediated cell death. J Biol Chem 283: 23179–23188. 44. Azeredo da Silveira S, Schneider BL, Cifuentes-Diaz C, Sage D, Abbas-Terki T, et al. (2009) Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson’s disease. Hum Mol Genet 18: 872–887. 45. Yamada M, Iwatsubo T, Mizuno Y, Mochizuki (2004) Overexpression of alpha- synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson’s disease. J Neurochem 91: 451–461. 46. Waxman EA, Giasson BI (2008) Specificity and regulation of casein kinase- mediated phosphorylation of alpha-synuclein. J Neuropathol Exp Neurol 67: 402–416. 47. Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, et al. (2002) Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem 277: 49071–49076. 48. Corti O, Hampe C, Koutnikova H, Darios F, Jacquier S, et al. (2003) The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum Mol Genet 12: 1427–1437. 49. Trinh K, Moore K, Wes PD, Muchowski PJ, Dey J, et al. (2008) Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson’s disease. J Neurosci 28: 465–472. 50. Zeevalk GD, Razmpour R, Bernard LP (2008) Glutathione and Parkinson’s disease: is this the elephant in the room? Biomed Pharmacother 62: 236–249. 51. von Coelln R, Thomas B, Andrabi SA, Lim KL, Savitt JM, et al. (2006) Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy. J Neurosci 26: 3685–3696. 52. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, et al. (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97: 571–576. 53. Kahle PJ, Neumann M, Ozmen L, Muller V, Odoy S, et al. (2001) Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 159: 2215–2225. 54. Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci 23: 3316–3324. PLoS ONE | www.plosone.org 13 August 2009 | Volume 4 | Issue 8 | e6629