Posttranslational modifications and clearing of α-synuclein aggregates in yeast

Biomolecules

Volumn 5, Issue 2, 2015, Pages 617-634

  Popova, Blagovesta ^a,b   Kleinknecht, Alexandra ^a,b   Braus, Gerhard H ^a,b  

^a UNIVERSITY OF GÖTTINGEN   (Germany)

^b Center for Nanoscale Microscopy and Molecular Physiology of the Brain   (Germany)

Author keywords

Aggregate clearance; Autophagy; Parkinson s disease; Posttranslational modifications; Proteasome; Yeast; synuclein

Indexed keywords

ALPHA SYNUCLEIN; PROTEASOME; SUMO 1 PROTEIN; SUMO 2 PROTEIN; SUMO 3 PROTEIN; UBIQUITIN; PROTEIN AGGREGATE;

AUTOPHAGY; CELL DEATH; CELL INCLUSION; CYTOTOXICITY; HUMAN; LYSOSOME; NONHUMAN; PARKINSON DISEASE; PHOSPHORYLATION; PROTEIN AGGREGATION; PROTEIN DEGRADATION; PROTEIN LOCALIZATION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; SUMOYLATION; YEAST; GENETICS; METABOLISM; SACCHAROMYCES CEREVISIAE;

SACCHAROMYCES CEREVISIAE; SACCHAROMYCETALES;

ALPHA-SYNUCLEIN; HUMANS; PARKINSON DISEASE; PROTEIN AGGREGATES; PROTEIN PROCESSING, POST-TRANSLATIONAL; SACCHAROMYCES CEREVISIAE; SUMOYLATION;

EID: 85012081847     PISSN: None     EISSN: 2218273X     Source Type: Journal    
DOI: 10.3390/biom5020617     Document Type: Review

References (117)

1. De Rijk, M.C.; Launer, L.J.; Berger, K.; Breteler, M.M.; Dartigues, J.F.; Baldereschi, M.; Fratiglioni, L.; Lobo, A.; Martinez-Lage, J.; Trenkwalder, C.; et al. Prevalence of Parkinson's disease in europe: A collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology 2000, 54, S21-S23.
2. Galvin, J.E.; Lee, V.M.; Trojanowski, J.Q. Synucleinopathies: Clinical and pathological implications. Arch. Neurol. 2001, 58, 186-190.
3. German, D.C.; Manaye, K.; Smith, W.K.; Woodward, D.J.; Saper, C.B. Midbrain dopaminergic cell loss in Parkinson's disease: Computer visualization. Ann. Neurol. 1989, 26, 507-514.
4. Fearnley, J.M.; Lees, A.J. Ageing and Parkinson's disease: Substantia nigra regional selectivity. Brain 1991, 114, 2283-2301.
5. Gibb, W.R.; Lees, A.J. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 1988, 51, 745-752.
6. Polymeropoulos, M.H.; Lavedan, C.; Leroy, E.; Ide, S.E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997, 276, 2045-2047.
7. Kruger, R.; Kuhn, W.; Muller, T.; Woitalla, D.; Graeber, M.; Kosel, S.; Przuntek, H.; Epplen, J.T.; Schols, L.; Riess, O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat. Genet. 1998, 18, 106-108.
8. Zarranz, J.J.; Alegre, J.; Gomez-Esteban, J.C.; Lezcano, E.; Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atares, B.; et al. The new mutation, E46K, of alpha-synuclein causes parkinson and Lewy body dementia. Ann. Neurol. 2004, 55, 164-173.
9. Singleton, A.B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague, S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum, R.; et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science 2003, doi:10.1126/science.1090278.
10. Athanassiadou, A.; Voutsinas, G.; Psiouri, L.; Leroy, E.; Polymeropoulos, M.H.; Ilias, A.; Maniatis, G.M.; Papapetropoulos, T. Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding alpha-synuclein. Am. J. Hum. Genet. 1999, 65, 555-558.
11. Lesage, S.; Anheim, M.; Letournel, F.; Bousset, L.; Honore, A.; Rozas, N.; Pieri, L.; Madiona, K.; Durr, A.; Melki, R.; et al. G51d α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann. Neurol. 2013, 73, 459-471.
12. Appel-Cresswell, S.; Vilarino-Guell, C.; Encarnacion, M.; Sherman, H.; Yu, I.; Shah, B.; Weir, D.; Thompson, C.; Szu-Tu, C.; Trinh, J.; et al. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov. Disord. 2013, 28, 811-813.
13. Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. Alpha-synuclein in Lewy bodies. Nature 1997, 388, 839-840.
14. Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Hasegawa, M.; Goedert, M. Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. USA 1998, 95, 6469-6473.
15. Goedert, M. Filamentous nerve cell inclusions in neurodegenerative diseases: Tauopathies and alpha-synucleinopathies. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1999, 354, 1101-1118.
16. Trojanowski, J.Q.; Goedert, M.; Iwatsubo, T.; Lee, V.M. Fatal attractions: Abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia. Cell Death Differ. 1998, 5, 832-837.
17. Maroteaux, L.; Campanelli, J.T.; Scheller, R.H. Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 1988, 8, 2804-2815.
18. Clayton, D.F.; George, J.M. The synucleins: A family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci. 1998, 21, 249-254.
19. Abeliovich, A.; Schmitz, Y.; Farinas, I.; Choi-Lundberg, D.; Ho, W.H.; Castillo, P.E.; Shinsky, N.; Verdugo, J.M.; Armanini, M.; Ryan, A.; et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 2000, 25, 239-252.
20. Golovko, M.Y.; Barcelo-Coblijn, G.; Castagnet, P.I.; Austin, S.; Combs, C.K.; Murphy, E.J. The role of alpha-synuclein in brain lipid metabolism: A downstream impact on brain inflammatory response. Mol. Cell. Biochem. 2009, 326, 55-66.
21. Burre, J.; Sharma, M.; Tsetsenis, T.; Buchman, V.; Etherton, M.R.; Sudhof, T.C. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 329, 1663-1667.
22. Nemani, V.M.; Lu, W.; Berge, V.; Nakamura, K.; Onoa, B.; Lee, M.K.; Chaudhry, F.A.; Nicoll, R.A.; Edwards, R.H. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 2010, 65, 66-79.
23. Cabin, D.E.; Shimazu, K.; Murphy, D.; Cole, N.B.; Gottschalk, W.; McIlwain, K.L.; Orrison, B.; Chen, A.; Ellis, C.E.; Paylor, R.; et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J. Neurosci. 2002, 22, 8797-8807.
24. Feany, M.B.; Bender, W.W. A drosophila model of Parkinson's disease. Nature 2000, 404, 394-398.
25. Masliah, E.; Rockenstein, E.; Veinbergs, I.; Mallory, M.; Hashimoto, M.; Takeda, A.; Sagara, Y.; Sisk, A.; Mucke, L. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: Implications for neurodegenerative disorders. Science 2000, 287, 1265-1269.
26. Ding, T.T.; Lee, S.J.; Rochet, J.C.; Lansbury, P.T., Jr. Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry 2002, 41, 10209-10217.
27. Lashuel, H.A.; Petre, B.M.; Wall, J.; Simon, M.; Nowak, R.J.; Walz, T.; Lansbury, P.T., Jr. Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J. Mol. Biol. 2002, 322, 1089-1102.
28. Conway, K.A.; Harper, J.D.; Lansbury, P.T. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 1998, 4, 1318-1320.
29. Jo, E.; Fuller, N.; Rand, R.P.; St George-Hyslop, P.; Fraser, P.E. Defective membrane interactions of familial Parkinson's disease mutant A30P alpha-synuclein. J. Mol. Biol. 2002, 315, 799-807.
30. Conway, K.A.; Lee, S.J.; Rochet, J.C.; Ding, T.T.; Williamson, R.E.; Lansbury, P.T., Jr. 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 2000, 97, 571-576.
31. Ostrerova-Golts, N.; Petrucelli, L.; Hardy, J.; Lee, J.M.; Farer, M.; Wolozin, B. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 2000, 20, 6048-6054.
32. Lee, H.J.; Shin, S.Y.; Choi, C.; Lee, Y.H.; Lee, S.J. Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. J. Biol. Chem. 2002, 277, 5411-5417.
33. Yamin, G.; Glaser, C.B.; Uversky, V.N.; Fink, A.L. Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. J. Biol. Chem. 2003, 278, 27630-27635.
34. Vila, M.; Vukosavic, S.; Jackson-Lewis, V.; Neystat, M.; Jakowec, M.; Przedborski, S. α-Synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin mptp. J. Neurochem. 2000, 74, 721-729.
35. Hashimoto, M.; Hsu, L.J.; Xia, Y.; Takeda, A.; Sisk, A.; Sundsmo, M.; Masliah, E. Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro. Neuroreport 1999, 10, 717-721.
36. Sherer, T.B.; Betarbet, R.; Stout, A.K.; Lund, S.; Baptista, M.; Panov, A.V.; Cookson, M.R.; Greenamyre, J.T. An in vitro model of Parkinson's disease: Linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J. Neurosci. 2002, 22, 7006-7015.
37. Uversky, V.N.; Li, J.; Fink, A.L. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure. J. Biol. Chem. 2001, 276, 44284-44296.
38. Braak, H.; del Tredici, K.; Rub, U.; de Vos, R.A.; Jansen Steur, E.N.; Braak, E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 2003, 24, 197-211.
39. Desplats, P.; Lee, H.J.; Bae, E.J.; Patrick, C.; Rockenstein, E.; Crews, L.; Spencer, B.; Masliah, E.; Lee, S.J. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl. Acad. Sci. USA 2009, 106, 13010-13015.
40. Norris, E.H.; Giasson, B.I.; Ischiropoulos, H.; Lee, V.M. Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J. Biol. Chem. 2003, 278, 27230-27240.
41. Hodara, R.; Norris, E.H.; Giasson, B.I.; Mishizen-Eberz, A.J.; Lynch, D.R.; Lee, V.M.; Ischiropoulos, H. Functional consequences of alpha-synuclein tyrosine nitration: Diminished binding to lipid vesicles and increased fibril formation. J. Biol. Chem. 2004, 279, 47746-47753.
42. Oueslati, A.; Fournier, M.; Lashuel, H.A. Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: Implications for Parkinson's disease pathogenesis and therapies. Prog. Brain Res. 2010, 183, 115-145.
43. Chen, L.; Feany, M.B. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a drosophila model of Parkinson disease. Nat. Neurosci. 2005, 8, 657-663.
44. Lee, J.T.; Wheeler, T.C.; Li, L.; Chin, L.S. Ubiquitination of alpha-synuclein by SIAH-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum. Mol. Genet. 2008, 17, 906-917.
45. Hasegawa, M.; Fujiwara, H.; Nonaka, T.; Wakabayashi, K.; Takahashi, H.; Lee, V.M.; Trojanowski, J.Q.; Mann, D.; Iwatsubo, T. Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J. Biol. Chem. 2002, 277, 49071-49076.
46. Fujiwara, H.; Hasegawa, M.; Dohmae, N.; Kawashima, A.; Masliah, E.; Goldberg, M.S.; Shen, J.; Takio, K.; Iwatsubo, T. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 2002, 4, 160-164.
47. Anderson, J.P.; Walker, D.E.; Goldstein, J.M.; de Laat, R.; Banducci, K.; Caccavello, R.J.; Barbour, R.; Huang, J.; Kling, K.; Lee, M.; et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 2006, 281, 29739-29752.
48. Paleologou, K.E.; Oueslati, A.; Shakked, G.; Rospigliosi, C.C.; Kim, H.Y.; Lamberto, G.R.; Fernandez, C.O.; Schmid, A.; Chegini, F.; Gai, W.P.; et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J. Neurosci. 2010, 30, 3184-3198.
49. Waxman, E.A.; Giasson, B.I. Specificity and regulation of casein kinase-mediated phosphorylation of alpha-synuclein. J. Neuropathol. Exp. Neurol. 2008, 67, 402-416.
50. Wales, P.; Pinho, R.; Lazaro, D.F.; Outeiro, T.F. Limelight on alpha-synuclein: Pathological and mechanistic implications in neurodegeneration. J. Parkinsons Dis. 2013, 3, 415-459.
51. Botstein, D.; Chervitz, S.A.; Cherry, J.M. Yeast as a model organism. Science 1997, 277, 1259-1260.
52. Hughes, T.R. Yeast and drug discovery. Func. Integr. Genomics 2002, 2, 199-211.
53. Franssens, V.; Boelen, E.; Anandhakumar, J.; Vanhelmont, T.; Buttner, S.; Winderickx, J. Yeast unfolds the road map toward alpha-synuclein-induced cell death. Cell Death Differ. 2010, 17, 746-753.
54. Flower, T.R.; Chesnokova, L.S.; Froelich, C.A.; Dixon, C.; Witt, S.N. Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson's disease. J. Mol. Biol. 2005, 351, 1081-1100.
55. Witt, S.N.; Flower, T.R. Alpha-synuclein, oxidative stress and apoptosis from the perspective of a yeast model of Parkinson's disease. FEMS Yeast Res. 2006, 6, 1107-1116.
56. Dixon, C.; Mathias, N.; Zweig, R.M.; Davis, D.A.; Gross, D.S. Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast. Genetics 2005, 170, 47-59.
57. Cooper, A.A.; Gitler, A.D.; Cashikar, A.; Haynes, C.M.; Hill, K.J.; Bhullar, B.; Liu, K.; Xu, K.; Strathearn, K.E.; Liu, F.; et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 2006, 313, 324-328.
58. Soper, J.H.; Roy, S.; Stieber, A.; Lee, E.; Wilson, R.B.; Trojanowski, J.Q.; Burd, C.G.; Lee, V.M. Alpha-synuclein-induced aggregation of cytoplasmic vesicles in saccharomyces cerevisiae. Mol. Biol. Cell 2008, 19, 1093-1103.
59. Gitler, A.D.; Bevis, B.J.; Shorter, J.; Strathearn, K.E.; Hamamichi, S.; Su, L.J.; Caldwell, K.A.; Caldwell, G.A.; Rochet, J.C.; McCaffery, J.M.; et al. The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasis. Proc. Natl. Acad. Sci. USA 2008, 105, 145-150.
60. Buttner, S.; Bitto, A.; Ring, J.; Augsten, M.; Zabrocki, P.; Eisenberg, T.; Jungwirth, H.; Hutter, S.; Carmona-Gutierrez, D.; Kroemer, G.; et al. Functional mitochondria are required for alpha-synuclein toxicity in aging yeast. J. Biol. Chem. 2008, 283, 7554-7560.
61. Su, L.J.; Auluck, P.K.; Outeiro, T.F.; Yeger-Lotem, E.; Kritzer, J.A.; Tardiff, D.F.; Strathearn, K.E.; Liu, F.; Cao, S.; Hamamichi, S.; et al. Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models. Dis. Model. Mech. 2010, 3, 194-208.
62. Outeiro, T.F.; Lindquist, S. Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 2003, 302, 1772-1775.
63. Petroi, D.; Popova, B.; Taheri-Talesh, N.; Irniger, S.; Shahpasandzadeh, H.; Zweckstetter, M.; Outeiro, T.F.; Braus, G.H. Aggregate clearance of alpha-synuclein in saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. J. Biol. Chem. 2012, 287, 27567-27579.
64. Zabrocki, P.; Pellens, K.; Vanhelmont, T.; Vandebroek, T.; Griffioen, G.; Wera, S.; van Leuven, F.; Winderickx, J. Characterization of alpha-synuclein aggregation and synergistic toxicity with protein tau in yeast. Febs. J. 2005, 272, 1386-1400.
65. Chartier-Harlin, M.C.; Kachergus, J.; Roumier, C.; Mouroux, V.; Douay, X.; Lincoln, S.; Levecque, C.; Larvor, L.; Andrieux, J.; Hulihan, M.; et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004, 364, 1167-1169.
66. Lazaro, D.F.; Rodrigues, E.F.; Langohr, R.; Shahpasandzadeh, H.; Ribeiro, T.; Guerreiro, P.; Gerhardt, E.; Krohnert, K.; Klucken, J.; Pereira, M.D.; et al. Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation. PLOS Genet. 2014, 10, e1004741.
67. Shimura, H.; Schlossmacher, M.G.; Hattori, N.; Frosch, M.P.; Trockenbacher, A.; Schneider, R.; Mizuno, Y.; Kosik, K.S.; Selkoe, D.J. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: Implications for Parkinson's disease. Science 2001, 293, 263-269.
68. Giasson, B.I.; Duda, J.E.; Murray, I.V.; Chen, Q.; Souza, J.M.; Hurtig, H.I.; Ischiropoulos, H.; Trojanowski, J.Q.; Lee, V.M. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science 2000, 290, 985-989.
69. Dorval, V.; Fraser, P.E. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J. Biol. Chem. 2006, 281, 9919-9924.
70. Guerrero, E.; Vasudevaraju, P.; Hegde, M.L.; Britton, G.B.; Rao, K.S. Recent advances in α-synuclein functions, advanced glycation, and toxicity: Implications for Parkinson's disease. Mol. Neurobiol. 2013, 47, 525-536.
71. Bartels, T.; Choi, J.G.; Selkoe, D.J. Alpha-synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011, 477, 107-110.
72. Melchior, F.; Schergaut, M.; Pichler, A. SUMO: Ligases, isopeptidases and nuclear pores. Trends Biochem. Sci. 2003, 28, 612-618.
73. Meulmeester, E.; Melchior, F. Cell biology: SUMO. Nature 2008, 452, 709-711.
74. Long, X.; Griffith, L.C. Identification and characterization of a SUMO-1 conjugation system that modifies neuronal calcium/calmodulin-dependent protein kinase II in drosophila melanogaster. J. Biol. Chem. 2000, 275, 40765-40776.
75. Jones, D.; Crowe, E.; Stevens, T.A.; Candido, E.P. Functional and phylogenetic analysis of the ubiquitylation system in caenorhabditis elegans: Ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins. Genome Biol. 2002, doi:10.1186/gb-2001-3-1-research0002.
76. Giaever, G.; Chu, A.M.; Ni, L.; Connelly, C.; Riles, L.; Veronneau, S.; Dow, S.; Lucau-Danila, A.; Anderson, K.; Andre, B.; et al. Functional profiling of the saccharomyces cerevisiae genome. Nature 2002, 418, 387-391.
77. Harting, R.; Bayram, O.; Laubinger, K.; Valerius, O.; Braus, G.H. Interplay of the fungal sumoylation network for control of multicellular development. Mol. Microbiol. 2013, 90, 1125-1145.
78. Dorval, V.; Fraser, P.E. SUMO on the road to neurodegeneration. Biochim. Biophys. Acta 2007, 1773, 694-706.
79. Krumova, P.; Weishaupt, J.H. SUMOylation in neurodegenerative diseases. Cell. Mol. Life Sci. 2013, 70, 2123-2138.
80. Eckermann, K. SUMO and Parkinson's disease. Neuromol. Med. 2013, 15, 737-759.
81. Krumova, P.; Meulmeester, E.; Garrido, M.; Tirard, M.; Hsiao, H.H.; Bossis, G.; Urlaub, H.; Zweckstetter, M.; Kugler, S.; Melchior, F.; et al. Sumoylation inhibits alpha-synuclein aggregation and toxicity. J. Cell. Biol. 2011, 194, 49-60.
82. Shahpasandzadeh, H.; Popova, B.; Kleinknecht, A.; Fraser, P.E.; Outeiro, T.F.; Braus, G.H. Interplay between sumoylation and phosphorylation for protection against alpha-synuclein inclusions. J. Biol. Chem. 2014, 289, 31224-31240.
83. Mbefo, M.; Fares, M.B.; Paleologou, K.; Oueslati, A.; Yin, G.; Tenreiro, S.; Pinto, M.; Outeiro, T.; Zweckstetter, M.; Masliah, E.; et al. The Parkinson's disease mutant E46K enhances α-synuclein phosphorylation in mammalian cell-lines, in yeast and in vivo. J. Biol. Chem. 2015, 290, 9412-9427.
84. Tenreiro, S.; Eckermann, K.; Outeiro, T.F. Protein phosphorylation in neurodegeneration: Friend or foe? Front. Mol. Neurosci. 2014, doi:10.3389/fnmol.2014.00042.
85. Azeredo da Silveira, S.; Schneider, B.L.; Cifuentes-Diaz, C.; Sage, D.; Abbas-Terki, T.; Iwatsubo, T.; Unser, M.; Aebischer, P. Phosphorylation does not prompt, nor prevent, the formation of α-synuclein toxic species in a rat model of Parkinson's disease. Hum. Mol. Genet. 2009, 18, 872-887.
86. McFarland, N.R.; Fan, Z.; Xu, K.; Schwarzschild, M.A.; Feany, M.B.; Hyman, B.T.; McLean, P.J. Alpha-synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of Parkinson disease. J. Neuropathol. Exp. Neurol. 2009, 68, 515-524.
87. Freichel, C.; Neumann, M.; Ballard, T.; Muller, V.; Woolley, M.; Ozmen, L.; Borroni, E.; Kretzschmar, H.A.; Haass, C.; Spooren, W.; et al. Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice. Neurobiol. Aging 2007, 28, 1421-1435.
88. Gorbatyuk, O.S.; Li, S.; Sullivan, L.F.; Chen, W.; Kondrikova, G.; Manfredsson, F.P.; Mandel, R.J.; Muzyczka, N., The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc. Natl. Acad. Sci. USA 2008, 105, 763-768.
89. Kuwahara, T.; Tonegawa, R.; Ito, G.; Mitani, S.; Iwatsubo, T. Phosphorylation of alpha-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in caenorhabditis elegans. J. Biol. Chem. 2012, 287, 7098-7109.
90. Pronin, A.N.; Morris, A.J.; Surguchov, A.; Benovic, J.L. Synucleins are a novel class of substrates for g protein-coupled receptor kinases. J. Biol. Chem. 2000, 275, 26515-26522.
91. Oueslati, A.; Schneider, B.L.; Aebischer, P.; Lashuel, H.A. Polo-like kinase 2 regulates selective autophagic alpha-synuclein clearance and suppresses its toxicity in vivo. Proc. Natl. Acad. Sci. USA 2013, 110, E3945-E3954.
92. Qing, H.; Wong, W.; McGeer, E.G.; McGeer, P.L. LRRK2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem. Biophys. Res. Commun. 2009, 387, 149-152.
93. Inglis, K.J.; Chereau, D.; Brigham, E.F.; Chiou, S.S.; Schobel, S.; Frigon, N.L.; Yu, M.; Caccavello, R.J.; Nelson, S.; Motter, R.; et al. Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J. Biol. Chem. 2009, 284, 2598-2602.
94. Mbefo, M.K.; Paleologou, K.E.; Boucharaba, A.; Oueslati, A.; Schell, H.; Fournier, M.; Olschewski, D.; Yin, G.; Zweckstetter, M.; Masliah, E.; et al. Phosphorylation of synucleins by members of the polo-like kinase family. J. Biol. Chem. 2010, 285, 2807-2822.
95. Salvi, M.; Trashi, E.; Marin, O.; Negro, A.; Sarno, S.; Pinna, L.A. Superiority of PLK-2 as alpha-synuclein phosphorylating agent relies on unique specificity determinants. Biochem. Biophys. Res. Commun. 2012, 418, 156-160.
96. Arawaka, S.; Wada, M.; Goto, S.; Karube, H.; Sakamoto, M.; Ren, C.H.; Koyama, S.; Nagasawa, H.; Kimura, H.; Kawanami, T.; et al. The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease. J. Neurosci. 2006, 26, 9227-9238.
97. Wang, S.; Xu, B.; Liou, L.C.; Ren, Q.; Huang, S.; Luo, Y.; Zhang, Z.; Witt, S.N. Alpha-synuclein disrupts stress signaling by inhibiting polo-like kinase Cdc5/PLK2. Proc. Natl. Acad. Sci. USA 2012, 109, 16119-16124.
98. Gitler, A.D.; Chesi, A.; Geddie, M.L.; Strathearn, K.E.; Hamamichi, S.; Hill, K.J.; Caldwell, K.A.; Caldwell, G.A.; Cooper, A.A.; Rochet, J.C.; et al. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes park9 and manganese toxicity. Nat. Genet. 2009, 41, 308-315.
99. Zabrocki, P.; Bastiaens, I.; Delay, C.; Bammens, T.; Ghillebert, R.; Pellens, K.; de Virgilio, C.; van Leuven, F.; Winderickx, J. Phosphorylation, lipid raft interaction and traffic of alpha-synuclein in a yeast model for Parkinson. Biochim. Biophys. Acta 2008, 1783, 1767-1780.
100. Sancenon, V.; Lee, S.A.; Patrick, C.; Griffith, J.; Paulino, A.; Outeiro, T.F.; Reggiori, F.; Masliah, E.; Muchowski, P.J. Suppression of alpha-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context. Hum. Mol. Genet. 2012, 21, 2432-2449.
101. Tenreiro, S.; Reimao-Pinto, M.M.; Antas, P.; Rino, J.; Wawrzycka, D.; Macedo, D.; Rosado-Ramos, R.; Amen, T.; Waiss, M.; Magalhaes, F.; et al. Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson's disease. PLOS Genet. 2014, 10, e1004302.
102. Xilouri, M.; Brekk, O.R.; Stefanis, L. Alpha-synuclein and protein degradation systems: A reciprocal relationship. Mol. Neurobiol. 2013, 47, 537-551.
103. Vilchez, D.; Saez, I.; Dillin, A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 2014, doi:10.1038/ncomms6659.
104. Kuzuhara, S.; Mori, H.; Izumiyama, N.; Yoshimura, M.; Ihara, Y. Lewy bodies are ubiquitinated: A light and electron microscopic immunocytochemical study. Acta Neuropathol. 1988, 75, 345-353.
105. Ii, K.; Ito, H.; Tanaka, K.; Hirano, A. Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J. Neuropathol. Exp. Neurol. 1997, 56, 125-131.
106. Bennett, M.C.; Bishop, J.F.; Leng, Y.; Chock, P.B.; Chase, T.N.; Mouradian, M.M. Degradation of alpha-synuclein by proteasome. J. Biol. Chem. 1999, 274, 33855-33858.
107. Tofaris, G.K.; Layfield, R.; Spillantini, M.G. Alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett. 2001, 509, 22-26.
108. Lindersson, E.; Beedholm, R.; Hojrup, P.; Moos, T.; Gai, W.; Hendil, K.B.; Jensen, P.H. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J. Biol. Chem. 2004, 279, 12924-12934.
109. Chen, Q.; Thorpe, J.; Keller, J.N. Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability. J. Biol. Chem. 2005, 280, 30009-30017.
110. Zhang, N.Y.; Tang, Z.; Liu, C.W. Alpha-synuclein protofibrils inhibit 26S proteasome-mediated protein degradation: Understanding the cytotoxicity of protein protofibrils in neurodegenerative disease pathogenesis. J. Biol. Chem. 2008, 283, 20288-20298.
111. Sharma, N.; Brandis, K.A.; Herrera, S.K.; Johnson, B.E.; Vaidya, T.; Shrestha, R.; Debburman, S.K. Alpha-synuclein budding yeast model: Toxicity enhanced by impaired proteasome and oxidative stress. J. Mol. Neurosci. 2006, 28, 161-178.
112. Ebrahimi-Fakhari, D.; Cantuti-Castelvetri, I.; Fan, Z.; Rockenstein, E.; Masliah, E.; Hyman, B.T.; McLean, P.J.; Unni, V.K. Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of alpha-synuclein. J. Neurosci. 2011, 31, 14508-14520.
113. Rott, R.; Szargel, R.; Haskin, J.; Shani, V.; Shainskaya, A.; Manov, I.; Liani, E.; Avraham, E.; Engelender, S. Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. J. Biol. Chem. 2008, 283, 3316-3328.
114. Lee, H.J.; Khoshaghideh, F.; Patel, S.; Lee, S.J. Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci. 2004, 24, 1888-1896.
115. Webb, J.L.; Ravikumar, B.; Atkins, J.; Skepper, J.N.; Rubinsztein, D.C. Alpha-synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 2003, 278, 25009-25013.
116. Winslow, A.R.; Chen, C.W.; Corrochano, S.; Acevedo-Arozena, A.; Gordon, D.E.; Peden, A.A.; Lichtenberg, M.; Menzies, F.M.; Ravikumar, B.; Imarisio, S.; et al. Alpha-synuclein impairs macroautophagy: Implications for Parkinson's disease. J. Cell. Biol. 2010, 190, 1023-1037.
117. Rott, R.; Szargel, R.; Haskin, J.; Bandopadhyay, R.; Lees, A.J.; Shani, V.; Engelender, S. Alpha-synuclein fate is determined by USP9X-regulated monoubiquitination. Proc. Natl. Acad. Sci. USA 2011, 108, 18666-18671.