α-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers

Acta Neuropathologica

Volumn 112, Issue 3, 2006, Pages 237-251

  Beyer, Katrin ^a  

^a HOSPITAL UNIVERSITARI GERMANS TRIAS I PUJOL   (Spain)

Author keywords

Synuclein; Aggregation; Alternative splicing; Posttranslational modifications

Indexed keywords

ALPHA SYNUCLEIN; ISOPROTEIN; POLYAMINE; PROTEIN GLUTAMINE GAMMA GLUTAMYLTRANSFERASE; RNA; SUMO PROTEIN;

ALTERNATIVE RNA SPLICING; ALZHEIMER DISEASE; CELL CULTURE; DEGENERATIVE DISEASE; GENE DUPLICATION; GENE MUTATION; HUMAN; NERVE ENDING; NITRATION; OLIGOMERIZATION; OXIDATION; PARKINSON DISEASE; PATHOGENESIS; POINT MUTATION; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN CONFORMATION; PROTEIN EXPRESSION; PROTEIN FAMILY; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN SECONDARY STRUCTURE; PROTEIN STRUCTURE; REVIEW; SHY DRAGER SYNDROME; SYNAPSE; UBIQUITINATION;

ALPHA-SYNUCLEIN; ALTERNATIVE SPLICING; AMINO ACID SEQUENCE; ANIMALS; HUMANS; MOLECULAR SEQUENCE DATA; PHOSPHORYLATION; PROTEIN PROCESSING, POST-TRANSLATIONAL;

EID: 33747769942     PISSN: 00016322     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00401-006-0104-6     Document Type: Review

References (136)

1. Alves Da Costa C, Paitel E, Vincent B, Checler F (2002) Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson's disease. J Biol Chem 277:50980-50984
2. Andringa G, Lam KY, Chegary M, Wang X, Chase TN, Bennett MC (2004) Tissue transglutaminase catalyzes the formation of alpha-synuclein crosslinks in Parkinson's disease. FASEB J 18:932-934
3. Antony T, Hoyer W, Cherny D, Heim G, Jovin TM, Subramaniam V (2003) Cellular polyamines promote the aggregation of alpha-synuclein. J Biol Chem 278:3235-3240
4. Apetri MM, Maiti NC, Zagorski MG, Carey PR, Anderson VE (2006) Secondary structure of alpha-synuclein oligomers: Characterization by Raman and atomic force microscopy. J Mol Biol 355:63-71
5. Auvinen M, Paasinen A, Andersson LC, Holtta E (1992) Ornithine decarboxylase activity is critical for cell transformation. Nature 360:355-358
6. Babu JR, Geetha T, Wooten MW (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem 94:192-203
7. Bandopadhyay R, Kingsbury AE, Muqit MM, Harvey K, Reid AR, Kilford L, Engelender S, Schlossmacher MG, Wood NW, Latchman DS, Harvey RJ, Lees AJ (2005) Synphilin-1 and parkin show overlapping expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Neurobiol Dis 20:401-411
8. Barghorn S, Davies P, Mandelkow E (2004) Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro are based on beta-structure in the core domain. Biochemistry 43:1694-1703
9. Bennett MK, Miller KG, Scheller RH (1993) Casein kinase II phosphorylates the synaptic vesicle protein p65. J Neurosci 13:1701-1707
10. Bertoncini CW, Jung YS, Fernandez CO, Hoyer W, Griesinger C, Jovin TM, Zweckstetter M (2005) Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc Natl Acad Sci USA 102:1430-1435
11. Beyer K, Lao JI, Carrato C, Mate JL, Lopez D, Ferrer I, Ariza A (2004) Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Neuropathol Appl Neurobiol 30:601-607
12. Beyer K, Lao JI, Carrato C, Mate JL, Lopez D, Ferrer I, Ariza A (2004) Upregulation of amyloid precursor protein isoforms containing Kunitz protease inhibitor in dementia with Lewy bodies. Brain Res Mol Brain Res 131:131-135
13. Beyer K, Humbert J, Ferrer A, Lao JI, Carrato C, López D, Ferrer I, Ariza A (2006) Low a-synuclein 126 mRNA levels in dementia with Lewy bodies and Alzheimer disease. NeuroReport (in press)
14. Biere AL, Wood SJ, Wypych J, Steavenson S, Jiang Y, Anafi D, Jacobsen FW, Jarosinski MA, Wu GM, Louis JC, Martin F, Narhi LO, Citron M (2000) Parkinson's disease-associated alpha-synuclein is more fibrillogenic than beta- and gamma-synuclein and cannot cross-seed its homologs. J Biol Chem 275:34574-34579
15. Bisaglia M, Schievano E, Caporale A, Peggion E, Mammi S (2006) The 11-mer repeats of human alpha-synuclein in vesicle interactions and lipid composition discrimination: A cooperative role. Biopolymers 84:310-316
16. Britton FC, Wang GL, Huang ZM, Ye L, Horowitz B, Hume JR, Duan D (2005) Functional characterization of novel alternatively spliced ClC-2 chloride channel variants in the heart. J Biol Chem 280:25871-25880
17. Bussell R Jr, Eliezer D (2003) A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. J Mol Biol 329:763-778
18. Bussell R Jr, Eliezer D (2004) Effects of Parkinson's disease-linked mutations on the structure of lipid-associated alpha-synuclein. Biochemistry 43:4810-4818
19. Bussell R Jr, Ramlall TF, Eliezer D (2005) Helix periodicity, topology, and dynamics of membrane-associated alpha-synuclein. Protein Sci 14:862-872
20. Campion D, Martin C, Heilig R, Charbonnier F, Moreau V, Flaman JM, Petit JL, Hannequin D, Brice A, Frebourg T (1995) The NACP/synuclein gene: chromosomal assignment and screening for alterations in Alzheimer disease. Genomics 26:254-257
21. Chandra S, Chen X, Rizo J, Jahn R, Sudhof TC (2003) A broken alpha -helix in folded alpha-synuclein. J Biol Chem 278:15313-15318
22. 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, Destee A (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364:1167-1169
23. Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657-663
24. Choi W, Zibaee S, Jakes R, Serpell LC, Davletov B, Crowther RA, Goedert M (2004) Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein. FEBS Lett 576:363-368
25. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: Implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144-1150
26. Citron BA, Suo Z, SantaCruz K, Davies PJ, Qin F, Festoff BW (2002) Protein crosslinking, tissue transglutaminase, alternative splicing and neurodegeneration. Neurochem Int 40:69-78
27. Clark RS, Bayir H, Jenkins LW (2005) Posttranslational protein modifications. Crit Care Med 33:S407-S409
28. Conway KA, Harper JD, Lansbury PT Jr (2000) Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry 39:2552-2563
29. Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294:1346-1349
30. Crowther RA, Jakes R, Spillantini MG, Goedert M (1998) Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett 436:309-312
31. David DC, Layfield R, Serpell L, Narain Y, Goedert M, Spillantini MG (2002) Proteasomal degradation of tau protein. J Neurochem 83:176-185
32. Davidson WS, Jonas A, Clayton DF, George JM (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443-9449
33. Dickson DW, Liu W, Hardy J, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T, Golbe L, Sage J, Sima A, D'Amato C, Albin R, Gilman S, Yen SH (1999) Widespread alterations of alpha-synuclein in multiple system atrophy. Am J Pathol 155:1241-1251
34. Dohmen RJ (2004) SUMO protein modification. Biochim Biophys Acta 1695:113-131
35. Dorval V, Fraser PE (2006) Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and {alpha}-synuclein. J Biol Chem 281:9919-9924
36. Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL (2006) Substrate-mediated enhancement of phosphorylated tyrosine hydroxylase in nigrostriatal dopamine neurons: Evidence for a role of alpha-synuclein. J Neurochem 96:950-959
37. Dudek SM, Johnson GV (1993) Transglutaminase catalyzes the formation of sodium dodecyl sulfate-insoluble, Alz-50-reactive polymers of tau. J Neurochem 61:1159-1162
38. 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
39. 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
40. 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
41. Fernandez CO, Hoyer W, Zweckstetter M, Jares-Erijman EA, Subramaniam V, Griesinger C, Jovin TM (2004) NMR of alpha-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO J 23:2039-2046
42. Ferrer I (2001) Alpha-synucleinopathies. Neurologia 16:163-170
43. Fisk HA, Yaffe MP (1999) A role for ubiquitination in mitochondrial inheritance in Saccharomyces cerevisiae. J Cell Biol 145:1199-1208
44. 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
45. 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
46. Giasson BI, Uryu K, Trojanowski JQ, Lee VM (1999) Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 274:7619-7622
47. 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
48. Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42:8465-8471
49. Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 280:7800-7807
50. Gross SD, Hoffman DP, Fisette PL, Baas P, Anderson RA (1995) A phosphatidylinositol 4,5-bisphosphate-sensitive casein kinase I alpha associates with synaptic vesicles and phosphorylates a subset of vesicle proteins. J Cell Biol 130:711-724
51. 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
52. Hodara R, Norris EH, Giasson BI, Mishizen-Eberz AJ, Lynch DR, Lee VM, Ischiropoulos H (2004) Functional consequences of alpha-synuclein tyrosine nitration: Diminished binding to lipid vesicles and increased fibril formation. J Biol Chem 279:47746-47753
53. Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 364:1169-1171
54. Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345:27-32
55. Jakes R, Crowther RA, Lee VM, Trojanowski JQ, Iwatsubo T, Goedert M (1999) Epitope mapping of LB509, a monoclonal antibody directed against human alpha-synuclein. Neurosci Lett 269:13-16
56. Jao CC, Der-Sarkissian A, Chen J, Langen R (2004) Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling. Proc Natl Acad Sci USA 101:8331-8336
57. Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6):S2-S12
58. 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
59. Jensen PH, Sorensen ES, Petersen TE, Gliemann J, Rasmussen LK (1995) Residues in the synuclein consensus motif of the alpha-synuclein fragment, NAC, participate in transglutaminase-catalysed cross-linking to Alzheimer-disease amyloid beta A4 peptide. Biochem J 310(Pt 1):91-94
60. Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M (1998) Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation. J Biol Chem 273:26292-26294
61. Jo E, McLaurin J, Yip CM, St George-Hyslop P, Fraser PE (2000) alpha-Synuclein membrane interactions and lipid specificity. J Biol Chem 275:34328-34334
62. Jo E, Darabie AA, Han K, Tandon A, Fraser PE, McLaurin J (2004) alpha-Synuclein-synaptosomal membrane interactions: Implications for fibrillogenesis. Eur J Biochem 271:3180-3189
63. Junn E, Ronchetti RD, Quezado MM, Kim SY, Mouradian MM (2003) Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 100:2047-2052
64. Karpuj MV, Garren H, Slunt H, Price DL, Gusella J, Becher MW, Steinman L (1999) Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei. Proc Natl Acad Sci USA 96:7388-7393
65. 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
66. 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
67. Lee HJ, Choi C, Lee SJ (2002) Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J Biol Chem 277:671-678
68. 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
69. 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
70. Leng Y, Chase TN, Bennett MC (2001) Muscarinic receptor stimulation induces translocation of an alpha-synuclein oligomer from plasma membrane to a light vesicle fraction in cytoplasm. J Biol Chem 276:28212-28218
71. Li J, Uversky VN, Fink AL (2001) Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. Biochemistry 40:11604-11613
72. Li W, Lesuisse C, Xu Y, Troncoso JC, Price DL, Lee MK (2004) Stabilization of alpha-synuclein protein with aging and familial Parkinson's disease-linked A53T mutation. J Neurosci 24:7400-7409
73. Li W, West N, Colla E, Pletnikova O, Troncoso JC, Marsh L, Dawson TM, Jakala P, Hartmann T, Price DL, Lee MK (2005) Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations. Proc Natl Acad Sci USA 102:2162-2167
74. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R, Engelender S (2004) Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Proc Natl Acad Sci USA 101:5500-5505
75. Lim KL, Chew KC, Tan JM, Wang C, Chung KK, Zhang Y, Tanaka Y, Smith W, Engelender S, Ross CA, Dawson VL, Dawson TM (2005) Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci 25:2002-2009
76. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 111:209-218
77. Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ (2005) A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: Implications for pathogenesis of Parkinson disease. J Biol Chem 280:22670-22678
78. Lotharius J, Brundin P (2002) Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum Mol Genet 11:2395-2407
79. Melchior F, Schergaut M, Pichler A (2003) SUMO: Ligases, isopeptidases and nuclear pores. Trends Biochem Sci 28:612-618
80. Morrison LD, Cao XC, Kish SJ (1998) Ornithine decarboxylase in human brain: Influence of aging, regional distribution, and Alzheimer's disease. J Neurochem 71:288-294
81. 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
82. 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
83. Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M (1999) Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 274:9843-9846
84. Nishie M, Mori F, Fujiwara H, Hasegawa M, Yoshimoto M, Iwatsubo T, Takahashi H, Wakabayashi K (2004) Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol (Berl) 107:292-298
85. Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, Kitami T, Sato K, Kuroda R, Tomiyama H, Mizoguchi K, Murata M, Toda T, Imoto I, Inazawa J, Mizuno Y, Hattori N (2006) Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol 59:298-309
86. Nonaka T, Iwatsubo T, Hasegawa M (2005) Ubiquitination of alpha-synuclein. Biochemistry 44:361-368
87. Norlund MA, Lee JM, Zainelli GM, Muma NA (1999) Elevated transglutaminase-induced bonds in PHF tau in Alzheimer's disease. Brain Res 851:154-163
88. Norris EH, Giasson BI, Ischiropoulos H, Lee VM (2003) Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J Biol Chem 278:27230-27240
89. Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H, Lee VM (2005) Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations. J Biol Chem 280:21212-21219
90. 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
91. Ono K, Yamada M (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem 97:105-115
92. 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
93. Padron D, Tall RD, Roth MG (2006) Phospholipase D2 is required for efficient endocytic recycling of transferrin receptors. Mol Biol Cell 17:598-606
94. Paik SR, Shin HJ, Lee JH (2000) Metal-catalyzed oxidation of alpha-synuclein in the presence of Copper(II) and hydrogen peroxide. Arch Biochem Biophys 378:269-277
95. Pan DN, Li JJ, Wei L, Yao M, Wan DF, Gu JR (2005) Inhibitory effect of CT120B, an alternative splice variant of CT120A, on lung cancer cell growth. Acta Biochim Biophys Sin (Shanghai) 37:588-592
96. Pandey N, Schmidt RE, Galvin JE (2006) The alpha-synuclein mutation E46K promotes aggregation in cultured cells. Exp Neurol 197:515-520
97. 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
98. Perrin RJ, Woods WS, Clayton DF, George JM (2000) Interaction of human alpha-Synuclein and Parkinson's disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J Biol Chem 275:34393-34398
99. Perrin RJ, Woods WS, Clayton DF, George JM (2001) Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 276:41958-41962
100. Petersen K, Olesen OF, Mikkelsen JD (1999) Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortex. Neuroscience 91:651-659
101. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13:703-714
102. Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70:503-533
103. 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
104. Pountney DL, Huang Y, Burns RJ, Haan E, Thompson PD, Blumbergs PC, Gai WP (2003) SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease. Exp Neurol 184:436-446
105. Pountney DL, Chegini F, Shen X, Blumbergs PC, Gai WP (2005) SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy. Neurosci Lett 381:74-79
106. Powner DJ, Payne RM, Pettitt TR, Giudici ML, Irvine RF, Wakelam MJ (2005) Phospholipase D2 stimulates integrin-mediated adhesion via phosphatidylinositol 4-phosphate 5-kinase Igamma b. J Cell Sci 118:2975-2986
107. Preece P, Cairns NJ (2003) Quantifying mRNA in postmortem human brain: influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance. Brain Res Mol Brain Res 118:60-71
108. 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
109. Rasmussen LK, Sorensen ES, Petersen TE, Gliemann J, Jensen PH (1994) Identification of glutamine and lysine residues in Alzheimer amyloid beta A4 peptide responsible for transglutaminase-catalysed homopolymerization and cross-linking to alpha 2M receptor. FEBS Lett 338:161-166
110. Riley BE, Zoghbi HY, Orr HT (2005) SUMOylation of the polyglutamine repeat protein, ataxin-1, is dependent on a functional nuclear localization signal. J Biol Chem 280:21942-21948
111. Sakamoto M, Uchihara T, Nakamura A, Mizutani T, Mizusawa H (2005) Progressive accumulation of ubiquitin and disappearance of alpha-synuclein epitope in multiple system atrophy-associated glial cytoplasmic inclusions: Triple fluorescence study combined with Gallyas-Braak method. Acta Neuropathol (Berl) 110:417-425
112. 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
113. Serpell LC, Berriman J, Jakes R, Goedert M, Crowther RA (2000) Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci USA 97:4897-4902
114. 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 alpha-synuclein by parkin from human brain: Implications for Parkinson's disease. Science 293:263-269
115. Shinbo Y, Niki T, Taira T, Ooe H, Takahashi-Niki K, Maita C, Seino C, Iguchi-Ariga SM, Ariga H (2006) Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities. Cell Death Differ 13:96-108
116. Sidhu A, Wersinger C, Vernier P (2004) alpha-Synuclein regulation of the dopaminergic transporter: A possible role in the pathogenesis of Parkinson's disease. FEBS Lett 565:1-5
117. 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
118. Smith WW, Jiang H, Pei Z, Tanaka Y, Morita H, Sawa A, Dawson VL, Dawson TM, Ross CA (2005) Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum Mol Genet 14:3801-3811
119. Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, Dawson VL, Dawson TM, Iwatsubo T, Ross CA (2005) Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 25:5544-5552
120. Souza JM, Giasson BI, Chen Q, Lee VM, Ischiropoulos H (2000) Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem 275:18344-18349
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 27:379-381
122. Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC, Slepko N, Illes K, Lukacsovich T, Zhu YZ, Cattaneo E, Pandolfi PP, Thompson LM, Marsh JL (2004) SUMO modification of Huntingtin and Huntington's disease pathology. Science 304:100-104
123. 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
124. Tofaris GK, Layfield R, Spillantini MG (2001) alpha-Synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509:22-26
125. 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
126. Trojanowski JQ, Lee VM (2003) Parkinson's disease and related alpha-synucleinopathies are brain amyloidoses. Ann N Y Acad Sci 991:107-110
127. Tzivion G, Luo Z, Avruch J (1998) A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Nature 394:88-92
128. 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
129. Ueda H, Goto J, Hashida H, Lin X, Oyanagi K, Kawano H, Zoghbi HY, Kanazawa I, Okazawa H (2002) Enhanced SUMOylation in polyglutamine diseases. Biochem Biophys Res Commun 293:307-313
130. Unger EL, Eve DJ, Perez XA, Reichenbach DK, Xu Y, Lee MK, Andrews AM (2006) Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human alpha-synuclein in mice. Neurobiol Dis 21:431-443
131. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412:346-351
132. 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
133. Wenning GK, Jellinger KA (2005) The role of alpha-synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathol (Berl) 109:129-140
134. Yavich L, Tanila H, Vepsalainen S, Jakala P (2004) Role of alpha-synuclein in presynaptic dopamine recruitment. J Neurosci 24:11165-11170
135. You J, Pickart CM (2001) A HECT domain E3 enzyme assembles novel polyubiquitin chains. J Biol Chem 276:19871-19878
136. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, 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