Alpha-synuclein at the intracellular and the extracellular side: Functional and dysfunctional implications

Biological Chemistry

Volumn 398, Issue 1, 2017, Pages 77-100

  Ottolini, Denis ^a   Calí, Tito ^a   Szabò, Ildikò ^a   Brini, Marisa ^a  

^a UNIVERSITY OF PADOVA   (Italy)

Author keywords

alpha synuclein; familial mutations; neurodegeneration; Parkinson's disease

Indexed keywords

ALPHA SYNUCLEIN; MONOMER; OLIGOMER; PROTEASOME; PROTEIN AGGREGATE; UBIQUITIN;

AUTOPHAGY; CELL MIGRATION; CHANNEL GATING; CYTOTOXICITY; ENDOPLASMIC RETICULUM; EXTRACELLULAR SPACE; GENETIC LINKAGE; HUMAN; INTRACELLULAR SPACE; MITOCHONDRION; NITRATION; NONHUMAN; PARKINSON DISEASE; POINT MUTATION; PRIORITY JOURNAL; PROTEIN ACETYLATION; PROTEIN AGGREGATION; PROTEIN PHOSPHORYLATION; PROTEIN SECRETION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION; SUMOYLATION; SYNAPTIC TRANSMISSION; UBIQUITINATION; ANIMAL; CHEMISTRY; GENETICS; METABOLISM; MUTATION; PROTEIN MULTIMERIZATION;

ALPHA-SYNUCLEIN; ANIMALS; EXTRACELLULAR SPACE; HUMANS; INTRACELLULAR SPACE; MUTATION; PROTEIN AGGREGATES; PROTEIN MULTIMERIZATION;

EID: 85002792350     PISSN: 14316730     EISSN: 14374315     Source Type: Journal    
DOI: 10.1515/hsz-2016-0201     Document Type: Review

References (289)

1. 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. (2000). Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239-252.
2. Agnati, L.F., Guidolin, D., Baluska, F., Leo, G., Barlow, P.W., Carone, C., and Genedani, S. (2010). A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: possible relevance for Alzheimer's disease. Curr. Alzheimer Res. 7, 307-322.
3. 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. (2006). Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739-29752.
4. Angot, E. and Brundin, P. (2009). Dissecting the potential molecular mechanisms underlying α-synuclein cell-to-cell transfer in Parkinson's disease. Parkinsonism Relat. Disord. 15(Suppl. 3), S143-S147.
5. Angot, E., Steiner, J.A., Hansen, C., Li, J.Y., and Brundin, P. (2010). Are synucleinopathies prion-like disorders? Lancet Neurol. 9, 1128-1138.
6. Angot, E., Steiner, J.A., Lema Tome, C.M., Ekstrom, P., Mattsson, B., Bjorklund, A., and Brundin, P. (2012). Alpha-synuclein cell-tocell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 7, e39465.
7. 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. (2013). Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov. Disord. 28, 811-813.
8. Area-Gomez, E., Del Carmen Lara Castillo, M., Tambini, M.D., Guardia-Laguarta, C., de Groof, A.J., Madra, M., Ikenouchi, J., Umeda, M., Bird, T.D., Sturley, S.L., et al. (2012). Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 31, 4106-4123.
9. Auluck, P.K., Caraveo, G., and Lindquist, S. (2010). Alpha-Synuclein: membrane interactions and toxicity in Parkinson's disease. Annu. Rev. Cell Dev. Biol. 26, 211-233.
10. Azeredo da Silveira, S., Schneider, B.L., Cifuentes-Diaz, C., Sage, D., Abbas-Terki, T., Iwatsubo, T., Unser, M., and Aebischer, P. (2009). Phosphorylation does not prompt, nor prevent, the formation of α-synuclein toxic species in a rat model of Parkinson's disease. Hum. Mol. Genet. 18, 872-887.
11. Bachhuber, T., Katzmarski, N., McCarter, J.F., Loreth, D., Tahirovic, S., Kamp, F., Abou-Ajram, C., Nuscher, B., Serrano-Pozo, A., Muller, A., et al. (2015). Inhibition of amyloid-α plaque formation by α-synuclein. Nat. Med. 21, 802-807.
12. Banigan, M.G., Kao, P.F., Kozubek, J.A., Winslow, A.R., Medina, J., Costa, J., Schmitt, A., Schneider, A., Cabral, H., Cagsal-Getkin, O., et al. (2013). Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One 8, e48814.
13. Bartels, T., Choi, J.G., and Selkoe, D.J. (2011). Alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107-110.
14. Bartels, T., Kim, N.C., Luth, E.S., and Selkoe, D.J. (2014). N-α- acetylation of α-synuclein increases its helical folding propensity, GM1 binding specificity and resistance to aggregation. PLoS One 9, e103727.
15. Bedford, L., Hay, D., Devoy, A., Paine, S., Powe, D.G., Seth, R., Gray, T., Topham, I., Fone, K., Rezvani, N., et al. (2008). Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J. Neurosci 28, 8189-8198.
16. Bennett, M.C., Bishop, J.F., Leng, Y., Chock, P.B., Chase, T.N., and Mouradian, M.M. (1999). Degradation of α-synuclein by proteasome. J. Biol. Chem. 274, 33855-33858.
17. Bernardi, P., Rasola, A., Forte, M., and Lippe, G. (2015). The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol. Rev. 95, 1111-1155.
18. Beyer, K. and Ariza, A. (2013). Alpha-Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration. Mol. Neurobiol. 47, 509-524.
19. Borghi, R., Marchese, R., Negro, A., Marinelli, L., Forloni, G., Zaccheo, D., Abbruzzese, G., and Tabaton, M. (2000). Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci. Lett. 287, 65-67.
20. Bousset, L., Pieri, L., Ruiz-Arlandis, G., Gath, J., Jensen, P.H., Habenstein, B., Madiona, K., Olieric, V., Bockmann, A., Meier, B.H., et al. (2013). Structural and functional characterization of two α-synuclein strains. Nat. Commun. 4, 2575.
21. Braak, H., Del Tredici, K., Rub, U., de Vos, R.A., Jansen Steur, E.N., and Braak, E. (2003a). Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197-211.
22. Braak, H., Rub, U., and Del Tredici, K. (2006). Cognitive decline correlates with neuropathological stage in Parkinson's disease. J. Neurol. Sci. 248, 255-258.
23. Braak, H., Rub, U., Gai, W.P., and Del Tredici, K. (2003b). Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural. Transm. (Vienna) 110, 517-536.
24. Burre, J., Sharma, M., and Sudhof, T.C. (2014). Alpha-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc. Natl. Acad. Sci. USA 111, E4274-E4283.
25. Burre, J., Sharma, M., and Sudhof, T.C. (2015). Definition of a molecular pathway mediating α-synuclein neurotoxicity. J. Neurosci. 35, 5221-5232.
26. Burre, J., Sharma, M., Tsetsenis, T., Buchman, V., Etherton, M.R., and Sudhof, T.C. (2010). Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663-1667.
27. 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. (2002). Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein. J. Neurosci. 22, 8797-8807.
28. Calí, T., Ottolini, D., Negro, A., and Brini, M. (2012). Alpha-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J. Biol. Chem. 287, 17914-17929.
29. Cardoso, S.M., Moreira, P.I., Agostinho, P., Pereira, C., and Oliveira, C.R. (2005). Neurodegenerative pathways in Parkinson's disease: therapeutic strategies. Curr. Drug. Targets CNS Neurol. Disord. 4, 405-419.
30. Chandra, S., Fornai, F., Kwon, H.B., Yazdani, U., Atasoy, D., Liu, X., Hammer, R.E., Battaglia, G., German, D.C., Castillo, P.E., et al. (2004). Double-knockout mice for α- and β-synucleins: effect on synaptic functions. Proc. Natl. Acad. Sci. USA 101, 14966-14971.
31. Chartier-Harlin, M.C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., et al. (2004). Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167-1169.
32. Chen, L. and Feany, M.B. (2005). Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci. 8, 657-663.
33. Chen, Q., Long, Y., Yuan, X., Zou, L., Sun, J., Chen, S., Perez-Polo, J.R., and Yang, K. (2005). Protective effects of bone marrow stromal cell transplantation in injured rodent brain: synthesis of neurotrophic factors. J. Neurosci. Res. 80, 611-619.
34. Chen, L., Periquet, M., Wang, X., Negro, A., McLean, P.J., Hyman, B.T., and Feany, M.B. (2009). Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J. Clin. Invest. 119, 3257-3265.
35. Chinta, S.J., Mallajosyula, J.K., Rane, A., and Andersen, J.K. (2010). Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci. Lett. 486, 235-239.
36. Choi, W., Zibaee, S., Jakes, R., Serpell, L.C., Davletov, B., Crowther, R.A., and Goedert, M. (2004). Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein. FEBS Lett. 576, 363-368.
37. Choubey, V., Safiulina, D., Vaarmann, A., Cagalinec, M., Wareski, P., Kuum, M., Zharkovsky, A., and Kaasik, A. (2011). Mutant A53T α-synuclein induces neuronal death by increasing mitochondrial autophagy. J. Biol. Chem. 286, 10814-10824.
38. Chu, Y. and Kordower, J.H. (2010). Lewy body pathology in fetal grafts. Ann. NY Acad. Sci. 1184, 55-67.
39. Chu, Y. and Kordower, J.H. (2015). The prion hypothesis of Parkinson's disease. Curr. Neurol. Neurosci. Rep. 15, 28.
40. Chu, Y., Goldman, J.G., Kelly, L., He, Y., Waliczek, T., and Kordower, J.H. (2014). Abnormal α-synuclein reduces nigral voltagedependent anion channel 1 in sporadic and experimental Parkinson's disease. Neurobiol Dis. 69, 1-14.
41. Chung, K.K., Zhang, Y., Lim, K.L., Tanaka, Y., Huang, H., Gao, J., Ross, C.A., Dawson, V.L., and Dawson, T.M. (2001). Parkin ubiquitinates the α-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat. Med. 7, 1144-1150.
42. Chung, C.Y., Khurana, V., Auluck, P.K., Tardiff, D.F., Mazzulli, J.R., Soldner, F., Baru, V., Lou, Y., Freyzon, Y., Cho, S., et al. (2013). Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983-987.
43. Colapinto, M., Mila, S., Giraudo, S., Stefanazzi, P., Molteni, M., Rossetti, C., Bergamasco, B., Lopiano, L., and Fasano, M. (2006). Alpha-Synuclein protects SH-SY5Y cells from dopamine toxicity. Biochem. Biophys. Res. Commun. 349, 1294-1300.
44. Conway, K.A., Harper, J.D., and Lansbury, P.T. (1998). Accelerated in vitro fibril formation by a mutant α-synuclein linked to earlyonset Parkinson disease. Nat. Med. 4, 1318-1320.
45. Conway, K.A., Lee, S.J., Rochet, J.C., Ding, T.T., Williamson, R.E., and Lansbury, P.T., Jr. (2000). Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc. Natl. Acad. Sci. USA 97, 571-576.
46. 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. (2006). Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313, 324-328.
47. Cramer, W.A., Zakharov, S.D., Saif Hasan, S., Zhang, H., Baniulis, D., Zhalnina, M.V., Soriano, G.M., Sharma, O., Rochet, J.C., Ryan, C., et al. (2011). Membrane proteins in four acts: function precedes structure determination. Methods 55, 415-420.
48. Crews, L., Spencer, B., Desplats, P., Patrick, C., Paulino, A., Rockenstein, E., Hansen, L., Adame, A., Galasko, D., and Masliah, E. (2010). Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of α-synucleinopathy. PLoS One 5, e9313.
49. Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T., and Sulzer, D. (2004). Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295.
50. Cuervo, A.M., Wong, E.S., and Martinez-Vicente, M. (2010). Protein degradation, aggregation, and misfolding. Mov. Disord. 25(Suppl 1), S49-S54.
51. da Costa, C.A., Ancolio, K., and Checler, F. (2000). Wild-type but not Parkinson's disease-related Ala-53 →Thr mutant α-synuclein protects neuronal cells from apoptotic stimuli. J. Biol. Chem. 275, 24065-24069.
52. Danzer, K.M., Kranich, L.R., Ruf, W.P., Cagsal-Getkin, O., Winslow, A.R., Zhu, L., Vanderburg, C.R., and McLean, P.J. (2012). Exosomal cell-to-cell transmission of α-synuclein oligomers. Mol. Neurodegener. 7, 42.
53. Dauer, W., Kholodilov, N., Vila, M., Trillat, A.C., Goodchild, R., Larsen, K.E., Staal, R., Tieu, K., Schmitz, Y., Yuan, C.A., et al. (2002). Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc. Natl. Acad. Sci. USA 99, 14524-14529.
54. Davidson, W.S., Jonas, A., Clayton, D.F., and George, J.M. (1998). Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273, 9443-9449.
55. De Vos, K.J., Grierson, A.J., Ackerley, S., and Miller, C.C. (2008). Role of axonal transport in neurodegenerative diseases. Annu. Rev. Neurosci. 31, 151-173.
56. Deng, H. and Yuan, L. (2014). Genetic variants and animal models in SNCA and Parkinson disease. Ageing Res. Rev. 15, 161-176.
57. Desplats, P., Lee, H.J., Bae, E.J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E., and Lee, S.J. (2009). Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl. Acad. Sci. USA 106, 13010-13015.
58. Dettmer, U., Newman, A.J., Soldner, F., Luth, E.S., Kim, N.C., von Saucken, V.E., Sanderson, J.B., Jaenisch, R., Bartels, T., and Selkoe, D. (2015). Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 6, 7314.
59. Devi, L., Raghavendran, V., Prabhu, B.M., Avadhani, N.G., and Anandatheerthavarada, H.K. (2008). Mitochondrial import and accumulation of α-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 283, 9089-9100.
60. Di Pasquale, E., Fantini, J., Chahinian, H., Maresca, M., Taieb, N., and Yahi, N. (2010). Altered ion channel formation by the Parkinson's-disease-linked E46K mutant of α-synuclein is corrected by GM3 but not by GM1 gangliosides. J. Mol. Biol. 397, 202-218.
61. Dikiy, I. and Eliezer, D. (2014). N-terminal acetylation stabilizes N-terminal helicity in lipid- and micelle-bound α-synuclein and increases its affinity for physiological membranes. J. Biol. Chem. 289, 3652-3665.
62. Dzamko, N., Zhou, J., Huang, Y., and Halliday, G.M. (2014). Parkinson's disease-implicated kinases in the brain; insights into disease pathogenesis. Front. Mol. Neurosci. 7, 57.
63. Dzamko, N., Geczy, C.L., and Halliday, G.M. (2015). Inflammation is genetically implicated in Parkinson's disease. Neuroscience 302, 89-102.
64. Ebrahimi-Fakhari, D., Cantuti-Castelvetri, I., Fan, Z., Rockenstein, E., Masliah, E., Hyman, B.T., McLean, P.J., and Unni, V.K. (2011). Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein. J. Neurosci. 31, 14508-14520.
65. El-Agnaf, O.M., Salem, S.A., Paleologou, K.E., Cooper, L.J., Fullwood, N.J., Gibson, M.J., Curran, M.D., Court, J.A., Mann, D.M., Ikeda, S., et al. (2003). Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 17, 1945-1947.
66. Eliezer, D., Kutluay, E., Bussell, R., Jr., and Browne, G. (2001). Conformational properties of α-synuclein in its free and lipidassociated states. J. Mol. Biol. 307, 1061-1073.
67. Emanuele, M. and Chieregatti, E. (2015). Mechanisms of α-synuclein action on neurotransmission: cell-autonomous and non-cell autonomous role. Biomolecules 5, 865-892.
68. Emmanouilidou, E., Melachroinou, K., Roumeliotis, T., Garbis, S.D., Ntzouni, M., Margaritis, L.H., Stefanis, L., and Vekrellis, K. (2010a). Cell-produced α-synuclein is secreted in a calciumdependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838-6851.
69. Emmanouilidou, E., Stefanis, L., and Vekrellis, K. (2010b). Cell-produced α-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol. Aging 31, 953-968.
70. Fares, M.B., Ait-Bouziad, N., Dikiy, I., Mbefo, M.K., Jovicic, A., Kiely, A., Holton, J.L., Lee, S.J., Gitler, A.D., Eliezer, D., et al. (2014). The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells. Hum. Mol. Genet. 23, 4491-4509.
71. Fauvet, B., Mbefo, M.K., Fares, M.B., Desobry, C., Michael, S., Ardah, M.T., Tsika, E., Coune, P., Prudent, M., Lion, N., et al. (2012). Alpha-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J. Biol. Chem. 287, 15345-15364.
72. Feng, L.R. and Maguire-Zeiss, K.A. (2011). Dopamine and paraquat enhance α-synuclein-induced alterations in membrane conductance. Neurotox. Res. 20, 387-401.
73. Feng, L.R., Federoff, H.J., Vicini, S., and Maguire-Zeiss, K.A. (2010). Alpha-synuclein mediates alterations in membrane conductance: a potential role for α-synuclein oligomers in cell vulnerability. Eur. J. Neurosci. 32, 10-17.
74. Fredenburg, R.A., Rospigliosi, C., Meray, R.K., Kessler, J.C., Lashuel, H.A., Eliezer, D., and Lansbury, P.T., Jr. (2007). The impact of the E46K mutation on the properties of α-synuclein in its monomeric and oligomeric states. Biochemistry 46, 7107-7118.
75. Freundt, E.C., Maynard, N., Clancy, E.K., Roy, S., Bousset, L., Sourigues, Y., Covert, M., Melki, R., Kirkegaard, K., and Brahic, M. (2012). Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport. Ann. Neurol. 72, 517-524.
76. Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M.S., Shen, J., Takio, K., and Iwatsubo, T. (2002). Alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160-164.
77. Furukawa, K., Matsuzaki-Kobayashi, M., Hasegawa, T., Kikuchi, A., Sugeno, N., Itoyama, Y., Wang, Y., Yao, P.J., Bushlin, I., and Takeda, A. (2006). Plasma membrane ion permeability induced by mutant α-synuclein contributes to the degeneration of neural cells. J. Neurochem. 97, 1071-1077.
78. Gallegos, S., Pacheco, C., Peters, C., Opazo, C.M., and Aguayo, L.G. (2015). Features of α-synuclein that could explain the progression and irreversibility of Parkinson's disease. Front Neurosci. 9, 59.
79. Geng, X., Lou, H., Wang, J., Li, L., Swanson, A.L., Sun, M., Beers- Stolz, D., Watkins, S., Perez, R.G., and Drain, P. (2011). Alpha-Synuclein binds the K(ATP) channel at insulin-secretory granules and inhibits insulin secretion. Am. J. Physiol. Endocrinol. Metab. 300, E276-E286.
80. George, J.M., Jin, H., Woods, W.S., and Clayton, D.F. (1995). Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15, 361-372.
81. George, S., Rey, N.L., Reichenbach, N., Steiner, J.A., and Brundin, P. (2013). Alpha-Synuclein: the long distance runner. Brain Pathol. 23, 350-357.
82. Ghosh, D., Sahay, S., Ranjan, P., Salot, S., Mohite, G.M., Singh, P.K., Dwivedi, S., Carvalho, E., Banerjee, R., Kumar, A., et al. (2014). The newly discovered Parkinson's disease associated Finnish mutation (A53E) attenuates α-synuclein aggregation and membrane binding. Biochemistry 53, 6419-6421.
83. Giasson, B.I., Duda, J.E., Murray, I.V., Chen, Q., Souza, J.M., Hurtig, H.I., Ischiropoulos, H., Trojanowski, J.Q., and Lee, V.M. (2000). Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science 290, 985-989.
84. Giasson, B.I., Forman, M.S., Higuchi, M., Golbe, L.I., Graves, C.L., Kotzbauer, P.T., Trojanowski, J.Q., and Lee, V.M. (2003). Initiation and synergistic fibrillization of tau and α-synuclein. Science 300, 636-640.
85. 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. (2008). The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasis. Proc. Natl. Acad. Sci. USA 105, 145-150.
86. Good, P.F., Hsu, A., Werner, P., Perl, D.P., and Olanow, C.W. (1998). Protein nitration in Parkinson's disease. J. Neuropathol. Exp. Neurol. 57, 338-342.
87. Greten-Harrison, B., Polydoro, M., Morimoto-Tomita, M., Diao, L., Williams, A.M., Nie, E.H., Makani, S., Tian, N., Castillo, P.E., Buchman, V.L., et al. (2010). αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc. Natl. Acad. Sci. USA 107, 19573-19578.
88. Grey, M., Dunning, C.J., Gaspar, R., Grey, C., Brundin, P., Sparr, E., and Linse, S. (2015). Acceleration of α-synuclein aggregation by exosomes. J. Biol. Chem. 290, 2969-2982.
89. Guardia-Laguarta, C., Area-Gomez, E., Rub, C., Liu, Y., Magrane, J., Becker, D., Voos, W., Schon, E.A., and Przedborski, S. (2014). Alpha-Synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 34, 249-259.
90. Guardia-Laguarta, C., Area-Gomez, E., Schon, E.A., and Przedborski, S. (2015). A new role for α-synuclein in Parkinson's disease: alteration of ER-mitochondrial communication. Mov. Disord. 30, 1026-1033.
91. Guo, J.L., Covell, D.J., Daniels, J.P., Iba, M., Stieber, A., Zhang, B., Riddle, D.M., Kwong, L.K., Xu, Y., Trojanowski, J.Q., et al. (2013). Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103-117.
92. Gurnev, P.A., Yap, T.L., Pfefferkorn, C.M., Rostovtseva, T.K., Berezhkovskii, A.M., Lee, J.C., Parsegian, V.A., and Bezrukov, S.M. (2014). Alpha-synuclein lipid-dependent membrane binding and translocation through the α-hemolysin channel. Biophys. J. 106, 556-565.
93. Gurry, T., Ullman, O., Fisher, C.K., Perovic, I., Pochapsky, T., and Stultz, C.M. (2013). The dynamic structure of α-synuclein multimers. J. Am. Chem. Soc. 135, 3865-3872.
94. Hall, S., Ohrfelt, A., Constantinescu, R., Andreasson, U., Surova, Y., Bostrom, F., Nilsson, C., Hakan, W., Decraemer, H., Nagga, K., et al. (2012). Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch. Neurol. 69, 1445-1452.
95. Hansen, C., Angot, E., Bergstrom, A.L., Steiner, J.A., Pieri, L., Paul, G., Outeiro, T.F., Melki, R., Kallunki, P., Fog, K., et al. (2011). Alpha- Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715-725.
96. Hasegawa, M., Fujiwara, H., Nonaka, T., Wakabayashi, K., Takahashi, H., Lee, V.M., Trojanowski, J.Q., Mann, D., and Iwatsubo, T. (2002). Phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions. J. Biol. Chem. 277, 49071-49076.
97. Hashimoto, M., Hsu, L.J., Rockenstein, E., Takenouchi, T., Mallory, M., and Masliah, E. (2002). Alpha-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. J. Biol. Chem. 277, 11465-11472.
98. Hawkes, C.H., Del Tredici, K., and Braak, H. (2009). Parkinson's disease: the dual hit theory revisited. Ann. N Y Acad. Sci. 1170, 615-622.
99. Hedskog, L., Pinho, C.M., Filadi, R., Ronnback, A., Hertwig, L., Wiehager, B., Larssen, P., Gellhaar, S., Sandebring, A., Westerlund, M., et al. (2013). Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models. Proc. Natl. Acad. Sci. USA 110, 7916-7921.
100. Hodara, R., Norris, E.H., Giasson, B.I., Mishizen-Eberz, A.J., Lynch, D.R., Lee, V.M., and Ischiropoulos, H. (2004). Functional consequences of α-synuclein tyrosine nitration: diminished binding to lipid vesicles and increased fibril formation. J. Biol. Chem. 279, 47746-47753.
101. Holmes, B.B., DeVos, S.L., Kfoury, N., Li, M., Jacks, R., Yanamandra, K., Ouidja, M.O., Brodsky, F.M., Marasa, J., Bagchi, D.P., et al. (2013). Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl. Acad. Sci. USA 110, E3138-E3147.
102. Holmqvist, S., Chutna, O., Bousset, L., Aldrin-Kirk, P., Li, W., Bjorklund, T., Wang, Z.Y., Roybon, L., Melki, R., and Li, J.Y. (2014). Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805-820.
103. Hsu, L.J., Sagara, Y., Arroyo, A., Rockenstein, E., Sisk, A., Mallory, M., Wong, J., Takenouchi, T., Hashimoto, M., and Masliah, E. (2000). Alpha-Synuclein promotes mitochondrial deficit and oxidative stress. Am. J. Pathol. 157, 401-410.
104. 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. (2009). Polo-like kinase 2 (PLK2) phosphorylates α-synuclein at serine 129 in central nervous system. J. Biol. Chem. 284, 2598-2602.
105. Irwin, D.J., Abrams, J.Y., Schonberger, L.B., Leschek, E.W., Mills, J.L., Lee, V.M., and Trojanowski, J.Q. (2013). Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 70, 462-468.
106. Ishii, A., Nonaka, T., Taniguchi, S., Saito, T., Arai, T., Mann, D., Iwatsubo, T., Hisanaga, S., Goedert, M., and Hasegawa, M. (2007). Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human α-synuclein: implication for α-synucleinopathies. FEBS Lett. 581, 4711-4717.
107. Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., de Silva, H.A., Kittel, A., and Saitoh, T. (1995). The precursor protein of non-Aβcomponent of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron 14, 467-475.
108. Jakes, R., Spillantini, M.G., and Goedert, M. (1994). Identification of two distinct synucleins from human brain. FEBS Lett. 345, 27-32.
109. Jang, A., Lee, H.J., Suk, J.E., Jung, J.W., Kim, K.P., and Lee, S.J. (2010). Non-classical exocytosis of α-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 113, 1263-1274.
110. Jensen, M.B., Bhatia, V.K., Jao, C.C., Rasmussen, J.E., Pedersen, S.L., Jensen, K.J., Langen, R., and Stamou, D. (2011). Membrane curvature sensing by amphipathic helices: a single liposome study using α-synuclein and annexin B12. J. Biol. Chem. 286, 42603-42614.
111. Jo, E., Fuller, N., Rand, R.P., St George-Hyslop, P., and Fraser, P.E. (2002). Defective membrane interactions of familial Parkinson's disease mutant A30P α-synuclein. J. Mol. Biol. 315, 799-807.
112. Kalia, L.V., Kalia, S.K., Chau, H., Lozano, A.M., Hyman, B.T., and McLean, P.J. (2011). Ubiquitinylation of α-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl- 2-associated athanogene 5 (BAG5). PLoS One 6, e14695.
113. Kalia, L.V., Kalia, S.K., McLean, P.J., Lozano, A.M., and Lang, A.E. (2013). Alpha-Synuclein oligomers and clinical implications for Parkinson disease. Ann. Neurol. 73, 155-169.
114. Kamp, F., Exner, N., Lutz, A.K., Wender, N., Hegermann, J., Brunner, B., Nuscher, B., Bartels, T., Giese, A., Beyer, K., et al. (2010). Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J. 29, 3571-3589.
115. Karpinar, D.P., Balija, M.B., Kugler, S., Opazo, F., Rezaei-Ghaleh, N., Wender, N., Kim, H.Y., Taschenberger, G., Falkenburger, B.H., Heise, H., et al. (2009). Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models. EMBO J. 28, 3256-3268.
116. Khalaf, O., Fauvet, B., Oueslati, A., Dikiy, I., Mahul-Mellier, A.L., Ruggeri, F.S., Mbefo, M.K., Vercruysse, F., Dietler, G., Lee, S.J., et al. (2014). The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity. J. Biol. Chem. 289, 21856-21876.
117. Kiely, A.P., Asi, Y.T., Kara, E., Limousin, P., Ling, H., Lewis, P., Proukakis, C., Quinn, N., Lees, A.J., Hardy, J., et al. (2013). Alpha-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy? Acta Neuropathol. 125, 753-769.
118. Kim, H.Y., Cho, M.K., Kumar, A., Maier, E., Siebenhaar, C., Becker, S., Fernandez, C.O., Lashuel, H.A., Benz, R., Lange, A., et al. (2009). Structural properties of pore-forming oligomers of α-synuclein. J. Am. Chem. Soc. 131, 17482-17489.
119. Kim, Y.M., Jang, W.H., Quezado, M.M., Oh, Y., Chung, K.C., Junn, E., and Mouradian, M.M. (2011). Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation. J. Neurol. Sci. 307, 157-161.
120. Kim, H.J., Jeon, B.S., Yoon, M.Y., Park, S.S., and Lee, K.W. (2012). Increased expression of α-synuclein by SNCA duplication is associated with resistance to toxic stimuli. J. Mol. Neurosci. 47, 249-255.
121. Klivenyi, P., Siwek, D., Gardian, G., Yang, L., Starkov, A., Cleren, C., Ferrante, R.J., Kowall, N.W., Abeliovich, A., and Beal, M.F. (2006). Mice lacking α-synuclein are resistant to mitochondrial toxins. Neurobiol. Dis. 21, 541-548.
122. Kordower, J.H., Chu, Y., Hauser, R.A., Freeman, T.B., and Olanow, C.W. (2008). Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat. Med. 14, 504-506.
123. Kordower, J.H., Dodiya, H.B., Kordower, A.M., Terpstra, B., Paumier, K., Madhavan, L., Sortwell, C., Steece-Collier, K., and Collier, T.J. (2011). Transfer of host-derived α-synuclein to grafted dopaminergic neurons in rat. Neurobiol. Dis. 43, 552-557.
124. Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J.T., Schols, L., and Riess, O. (1998). Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18, 106-108.
125. Krumova, P., and Weishaupt, J.H. (2013). Sumoylation in neurodegenerative diseases. Cell Mol. Life Sci. 70, 2123-2138.
126. Krumova, P., Meulmeester, E., Garrido, M., Tirard, M., Hsiao, H.H., Bossis, G., Urlaub, H., Zweckstetter, M., Kugler, S., Melchior, F., et al. (2011). Sumoylation inhibits α-synuclein aggregation and toxicity. J. Cell. Biol. 194, 49-60.
127. Kubo, S., Nemani, V.M., Chalkley, R.J., Anthony, M.D., Hattori, N., Mizuno, Y., Edwards, R.H., and Fortin, D.L. (2005). A combinatorial code for the interaction of α-synuclein with membranes. J. Biol. Chem. 280, 31664-31672.
128. Kurowska, Z., Englund, E., Widner, H., Lindvall, O., Li, J.Y., and Brundin, P. (2011). Signs of degeneration in 12-22-year old grafts of mesencephalic dopamine neurons in patients with Parkinson's disease. J. Parkinsons Dis. 1, 83-92.
129. Lamberts, J.T., Hildebrandt, E.N., and Brundin, P. (2015). Spreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: a speculative synthesis. Neurobiol. Dis. 77, 276-283.
130. Lashuel, H.A., Overk, C.R., Oueslati, A., and Masliah, E. (2013). The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14, 38-48.
131. 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. (2014). Systematic comparison of the effects of α-synuclein mutations on its oligomerization and aggregation. PLoS Genet 10, e1004741.
132. Lee, H.J., Khoshaghideh, F., Patel, S., and Lee, S.J. (2004a). Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci. 24, 1888-1896.
133. Lee, Y.J., Jeong, S.Y., Karbowski, M., Smith, C.L., and Youle, R.J. (2004b). Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell 15, 5001-5011.
134. Lee, H.J., Patel, S., and Lee, S.J. (2005). Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25, 6016-6024.
135. Lee, H.J., Suk, J.E., Bae, E.J., Lee, J.H., Paik, S.R., and Lee, S.J. (2008a). Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int. J. Biochem. Cell Biol. 40, 1835-1849.
136. Lee, H.J., Suk, J.E., Bae, E.J., and Lee, S.J. (2008b). Clearance and deposition of extracellular α-synuclein aggregates in microglia. Biochem. Biophys. Res. Commun. 372, 423-428.
137. Lee, J.T., Wheeler, T.C., Li, L., and Chin, L.S. (2008c). Ubiquitination of α-synuclein by Siah-1 promotes α-synuclein aggregation and apoptotic cell death. Hum. Mol. Genet. 17, 906-917.
138. Lee, H.J., Cho, E.D., Lee, K.W., Kim, J.H., Cho, S.G., and Lee, S.J. (2013). Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein. Exp. Mol. Med. 45, e22.
139. Lesage, S., Anheim, M., Letournel, F., Bousset, L., Honore, A., Rozas, N., Pieri, L., Madiona, K., Durr, A., Melki, R., et al. (2013). G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann. Neurol. 73, 459-471.
140. Levin, J., Schmidt, F., Boehm, C., Prix, C., Botzel, K., Ryazanov, S., Leonov, A., Griesinger, C., and Giese, A. (2014). The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 127, 779-780.
141. Li, W.W., Yang, R., Guo, J.C., Ren, H.M., Zha, X.L., Cheng, J.S., and Cai, D.F. (2007). Localization of α-synuclein to mitochondria within midbrain of mice. Neuroreport 18, 1543-1546.
142. Li, J.Y., Englund, E., Holton, J.L., Soulet, D., Hagell, P., Lees, A.J., Lashley, T., Quinn, N.P., Rehncrona, S., Bjorklund, A., et al. (2008). Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat. Med. 14, 501-503.
143. Li, J.Y., Englund, E., Widner, H., Rehncrona, S., Bjorklund, A., Lindvall, O., and Brundin, P. (2010). Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov. Disord. 25, 1091-1096.
144. Liani, E., Eyal, A., Avraham, E., Shemer, R., Szargel, R., Berg, D., Bornemann, A., Riess, O., Ross, C.A., Rott, R., et al. (2004). Ubiquitylation of synphilin-1 and α-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.
145. Lindersson, E., Beedholm, R., Hojrup, P., Moos, T., Gai, W., Hendil, K.B., and Jensen, P.H. (2004). Proteasomal inhibition by α-synuclein filaments and oligomers. J. Biol. Chem. 279, 12924-12934.
146. Liu, C.W., Corboy, M.J., DeMartino, G.N., and Thomas, P.J. (2003). Endoproteolytic activity of the proteasome. Science 299, 408-411.
147. Liu, T.T., Liu, Y.J., Wang, Q., Yang, X.G., and Wang, K. (2012). Reactive-oxygen-species-mediated Cdc25C degradation results in differential antiproliferative activities of vanadate, tungstate, and molybdate in the PC-3 human prostate cancer cell line. J. Biol. Inorg. Chem. 17, 311-320.
148. Liu, Q., Emadi, S., Shen, J.X., Sierks, M.R., and Wu, J. (2013). Human α4β2 nicotinic acetylcholine receptor as a novel target of oligomeric α-synuclein. PLoS One 8, e55886.
149. Lleo, A., Cavedo, E., Parnetti, L., Vanderstichele, H., Herukka, S.K., Andreasen, N., Ghidoni, R., Lewczuk, P., Jeromin, A., Winblad, B., et al. (2015). Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases. Nat. Rev. Neurol. 11, 41-55.
150. Loeb, V., Yakunin, E., Saada, A., and Sharon, R. (2010). The transgenic overexpression of α-synuclein and not its related pathology associates with complex I inhibition. J. Biol. Chem. 285, 7334-7343.
151. Lu, L., Zhang, C., Cai, Q., Lu, Q., Duan, C., Zhu, Y., and Yang, H. (2013). Voltage-dependent anion channel involved in the α-synuclein-induced dopaminergic neuron toxicity in rats. Acta Biochim. Biophys. Sin. (Shanghai) 45, 170-178.
152. Luk, K.C., Kehm, V., Carroll, J., Zhang, B., O'Brien, P., Trojanowski, J.Q., and Lee, V.M. (2012a). Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949-953.
153. Luk, K.C., Kehm, V.M., Zhang, B., O'Brien, P., Trojanowski, J.Q., and Lee, V.M. (2012b). Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209, 975-986.
154. Luth, E.S., Stavrovskaya, I.G., Bartels, T., Kristal, B.S., and Selkoe, D.J. (2014). Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+induced mitochondrial dysfunction. J. Biol. Chem. 289, 21490-21507.
155. Machiya, Y., Hara, S., Arawaka, S., Fukushima, S., Sato, H., Sakamoto, M., Koyama, S., and Kato, T. (2010). Phosphorylated α-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. J. Biol. Chem. 285, 40732-40744.
156. Mahul-Mellier, A.L., Vercruysse, F., Maco, B., Ait-Bouziad, N., De Roo, M., Muller, D., and Lashuel, H.A. (2015). Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. Cell Death Differ. 22, 2107-2122.
157. Mak, S.K., McCormack, A.L., Manning-Bog, A.B., Cuervo, A.M., and Di Monte, D.A. (2010). Lysosomal degradation of α-synuclein in vivo. J. Biol. Chem. 285, 13621-13629.
158. Maltsev, A.S., Ying, J., and Bax, A. (2012). Impact of N-terminal acetylation of α-synuclein on its random coil and lipid binding properties. Biochemistry 51, 5004-5013.
159. Maroteaux, L., Campanelli, J.T., and Scheller, R.H. (1988). Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 8, 2804-2815.
160. Martin, L.J., Pan, Y., Price, A.C., Sterling, W., Copeland, N.G., Jenkins, N.A., Price, D.L., and Lee, M.K. (2006). Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 26, 41-50.
161. Martin, L.J., Semenkow, S., Hanaford, A., and Wong, M. (2014). Mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice. Neurobiol. Aging 35, 1132-1152.
162. Martinez-Vicente, M., Talloczy, Z., Kaushik, S., Massey, A.C., Mazzulli, J., Mosharov, E.V., Hodara, R., Fredenburg, R., Wu, D.C., Follenzi, A., et al. (2008). Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. J. Clin. Invest. 118, 777-788.
163. Massey, A.C., Kaushik, S., Sovak, G., Kiffin, R., and Cuervo, A.M. (2006). Consequences of the selective blockage of chaperonemediated autophagy. Proc. Natl. Acad. Sci. USA 103, 5805-5810.
164. Masuda-Suzukake, M., Nonaka, T., Hosokawa, M., Oikawa, T., Arai, T., Akiyama, H., Mann, D.M., and Hasegawa, M. (2013). Prionlike spreading of pathological α-synuclein in brain. Brain 136, 1128-1138.
165. Masuda-Suzukake, M., Nonaka, T., Hosokawa, M., Kubo, M., Shimozawa, A., Akiyama, H., and Hasegawa, M. (2014). Pathological α-synuclein propagates through neural networks. Acta Neuropathol. Commun. 2, 88.
166. Mbefo, M.K., Paleologou, K.E., Boucharaba, A., Oueslati, A., Schell, H., Fournier, M., Olschewski, D., Yin, G., Zweckstetter, M., Masliah, E., et al. (2010). Phosphorylation of synucleins by members of the Polo-like kinase family. J. Biol. Chem. 285, 2807-2822.
167. Mbefo, M.K., Fares, M.B., Paleologou, K., Oueslati, A., Yin, G., Tenreiro, S., Pinto, M., Outeiro, T., Zweckstetter, M., Masliah, E., et al. (2015). Parkinson disease mutant E46K enhances α-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo. J. Biol. Chem. 290, 9412-9427.
168. Middleton, E.R., and Rhoades, E. (2010). Effects of curvature and composition on α-synuclein binding to lipid vesicles. Biophys. J. 99, 2279-2288.
169. Millecamps, S., and Julien, J.P. (2013). Axonal transport deficits and neurodegenerative diseases. Nat. Rev. Neurosci. 14, 161-176.
170. Mironov, S.L. (2015). Alpha-Synuclein forms non-selective cation channels and stimulates ATP-sensitive potassium channels in hippocampal neurons. J. Physiol. 593, 145-159.
171. Mittelbrunn, M., Vicente-Manzanares, M., and Sanchez-Madrid, F. (2015). Organizing polarized delivery of exosomes at synapses. Traffic 16, 327-337.
172. Mougenot, A.L., Nicot, S., Bencsik, A., Morignat, E., Verchere, J., Lakhdar, L., Legastelois, S., and Baron, T. (2012). Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225-2228.
173. Mullin, S. and Schapira, A. (2013). Alpha-Synuclein and mitochondrial dysfunction in Parkinson's disease. Mol. Neurobiol. 47, 587-597.
174. Murata, S., Minami, Y., Minami, M., Chiba, T., and Tanaka, K. (2001). CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep. 2, 1133-1138.
175. Nakamura, K., Nemani, V.M., Wallender, E.K., Kaehlcke, K., Ott, M., and Edwards, R.H. (2008). Optical reporters for the conformation of α-synuclein reveal a specific interaction with mitochondria. J. Neurosci. 28, 12305-12317.
176. Nakamura, K., Nemani, V.M., Azarbal, F., Skibinski, G., Levy, J.M., Egami, K., Munishkina, L., Zhang, J., Gardner, B., Wakabayashi, J., et al. (2011). Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein α-synuclein. J. Biol. Chem. 286, 20710-20726.
177. Nam, M.K., Han, J.H., Jang, J.Y., Yun, S.E., Kim, G.Y., Kang, S., and Rhim, H. (2015). A novel link between the conformations, exposure of specific epitopes, and subcellular localization of α-synuclein. Biochim. Biophys. Acta 1850, 2497-2505.
178. Nemani, M., Linares-Cruz, G., Bruzzoni-Giovanelli, H., Roperch, J.P., Tuynder, M., Bougueleret, L., Cherif, D., Medhioub, M., Pasturaud, P., Alvaro, V., et al. (1996). Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression. Proc. Natl. Acad. Sci. USA 93, 9039-9042.
179. Nemani, V.M., Lu, W., Berge, V., Nakamura, K., Onoa, B., Lee, M.K., Chaudhry, F.A., Nicoll, R.A., and Edwards, R.H. (2010). Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65, 66-79.
180. Nonaka, T., Iwatsubo, T., and Hasegawa, M. (2005). Ubiquitination of α-synuclein. Biochemistry 44, 361-368.
181. Norris, K.L., Hao, R., Chen, L.F., Lai, C.H., Kapur, M., Shaughnessy, P.J., Chou, D., Yan, J., Taylor, J.P., Engelender, S., et al. (2015). Convergence of Parkin, PINK1, and α-synuclein on stressinduced mitochondrial morphological remodeling. J. Biol. Chem. 290, 13862-13874.
182. Okochi, M., Walter, J., Koyama, A., Nakajo, S., Baba, M., Iwatsubo, T., Meijer, L., Kahle, P.J., and Haass, C. (2000). Constitutive phosphorylation of the Parkinson's disease associated α-synuclein. J. Biol. Chem. 275, 390-397.
183. Olanow, C.W. and Brundin, P. (2013). Parkinson's disease and α-synuclein: is Parkinson's disease a prion-like disorder? Mov. Disord. 28, 31-40.
184. Oueslati, A., Fournier, M., and Lashuel, H.A. (2010). Role of posttranslational modifications in modulating the structure, function and toxicity of α-synuclein: implications for Parkinson's disease pathogenesis and therapies. Prog. Brain Res. 183, 115-145.
185. Outeiro, T.F. and Lindquist, S. (2003). Yeast cells provide insight into α-synuclein biology and pathobiology. Science 302, 1772-1775.
186. Outeiro, T.F., Putcha, P., Tetzlaff, J.E., Spoelgen, R., Koker, M., Carvalho, F., Hyman, B.T., and McLean, P.J. (2008). Formation of toxic oligomeric α-synuclein species in living cells. PLoS One 3, e1867.
187. Pacheco, C.R., Morales, C.N., Ramirez, A.E., Munoz, F.J., Gallegos, S.S., Caviedes, P.A., Aguayo, L.G., and Opazo, C.M. (2015). Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane. J. Neurochem. 132, 731-741.
188. Paleologou, K.E., Kragh, C.L., Mann, D.M., Salem, S.A., Al-Shami, R., Allsop, D., Hassan, A.H., Jensen, P.H., and El-Agnaf, O.M. (2009). Detection of elevated levels of soluble α-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 132, 1093-1101.
189. 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. (2010). Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions. J. Neurosci. 30, 3184-3198.
190. Pan-Montojo, F., Anichtchik, O., Dening, Y., Knels, L., Pursche, S., Jung, R., Jackson, S., Gille, G., Spillantini, M.G., Reichmann, H., et al. (2010). Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One 5, e8762.
191. Parihar, M.S., Parihar, A., Fujita, M., Hashimoto, M., and Ghafourifar, P. (2008). Mitochondrial association of α-synuclein causes oxidative stress. Cell Mol. Life Sci. 65, 1272-1284.
192. Parnetti, L., Chiasserini, D., Persichetti, E., Eusebi, P., Varghese, S., Qureshi, M.M., Dardis, A., Deganuto, M., De Carlo, C., Castrioto, A., et al. (2014). Cerebrospinal fluid lysosomal enzymes and α-synuclein in Parkinson's disease. Mov. Disord. 29, 1019-1027.
193. Pasanen, P., Myllykangas, L., Siitonen, M., Raunio, A., Kaakkola, S., Lyytinen, J., Tienari, P.J., Poyhonen, M., and Paetau, A. (2014). Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology. Neurobiol. Aging 35, 2180 e2181-e2185.
194. Paumier, K.L., Luk, K.C., Manfredsson, F.P., Kanaan, N.M., Lipton, J.W., Collier, T.J., Steece-Collier, K., Kemp, C.J., Celano, S., Schulz, E., et al. (2015). Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol. Dis. 82, 185-199.
195. Paxinou, E., Chen, Q., Weisse, M., Giasson, B.I., Norris, E.H., Rueter, S.M., Trojanowski, J.Q., Lee, V.M., and Ischiropoulos, H. (2001). Induction of α-synuclein aggregation by intracellular nitrative insult. J. Neurosci. 21, 8053-8061.
196. Peelaerts, W., Bousset, L., Van der Perren, A., Moskalyuk, A., Pulizzi, R., Giugliano, M., Van den Haute, C., Melki, R., and Baekelandt, V. (2015). Alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340-344.
197. Petroi, D., Popova, B., Taheri-Talesh, N., Irniger, S., Shahpasandzadeh, H., Zweckstetter, M., Outeiro, T.F., and Braus, G.H. (2012). Aggregate clearance of α-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. J. Biol. Chem. 287, 27567-27579.
198. Petroski, M.D. and Deshaies, R.J. (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 6, 9-20.
199. Petrucelli, L., O'Farrell, C., Lockhart, P.J., Baptista, M., Kehoe, K., Vink, L., Choi, P., Wolozin, B., Farrer, M., Hardy, J., et al. (2002). Parkin protects against the toxicity associated with mutant α-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36, 1007-1019.
200. Pfefferkorn, C.M., Jiang, Z., and Lee, J.C. (2012). Biophysics of α-synuclein membrane interactions. Biochim. Biophys. Acta 1818, 162-171.
201. Pinotsi, D., Michel, C.H., Buell, A.K., Laine, R.F., Mahou, P., Dobson, C.M., Kaminski, C.F., and Kaminski Schierle, G.S. (2016). Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons. Proc. Natl. Acad. Sci. USA 113, 3815-3819.
202. Piper, R.C. and Katzmann, D.J. (2007). Biogenesis and function of multivesicular bodies. Annu. Rev. Cell Dev. Biol. 23, 519-547.
203. Plotegher, N., Gratton, E., and Bubacco, L. (2014). Number and Brightness analysis of α-synuclein oligomerization and the associated mitochondrial morphology alterations in live cells. Biochim. Biophys. Acta 1840, 2014-2024.
204. Poehler, A.M., Xiang, W., Spitzer, P., May, V.E., Meixner, H., Rockenstein, E., Chutna, O., Outeiro, T.F., Winkler, J., Masliah, E., et al. (2014). Autophagy modulates SNCA/α-synuclein release, thereby generating a hostile microenvironment. Autophagy 10, 2171-2192.
205. Polymeropoulos, M.H., Lavedan, C., Leroy, E., Ide, S.E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997). Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047.
206. Pountney, D.L., Chegini, F., Shen, X., Blumbergs, P.C., and Gai, W.P. (2005). SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy. Neurosci. Lett. 381, 74-79.
207. Pronin, A.N., Morris, A.J., Surguchov, A., and Benovic, J.L. (2000). Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J. Biol. Chem. 275, 26515-26522.
208. Prots, I., Veber, V., Brey, S., Campioni, S., Buder, K., Riek, R., Bohm, K.J., and Winner, B. (2013). Alpha-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J. Biol. Chem. 288, 21742-21754.
209. Proukakis, C., Dudzik, C.G., Brier, T., MacKay, D.S., Cooper, J.M., Millhauser, G.L., Houlden, H., and Schapira, A.H. (2013). A novel α-synuclein missense mutation in Parkinson disease. Neurology 80, 1062-1064.
210. Qing, H., Wong, W., McGeer, E.G., and McGeer, P.L. (2009). Lrrk2 phosphorylates α-synuclein at serine 129: Parkinson disease implications. Biochem. Biophys. Res. Commun. 387, 149-152.
211. Quist, A., Doudevski, I., Lin, H., Azimova, R., Ng, D., Frangione, B., Kagan, B., Ghiso, J., and Lal, R. (2005). Amyloid ion channels: a common structural link for protein-misfolding disease. Proc. Natl. Acad. Sci. USA 102, 10427-10432.
212. Rajendran, L., Bali, J., Barr, M.M., Court, F.A., Kramer-Albers, E.M., Picou, F., Raposo, G., van der Vos, K.E., van Niel, G., Wang, J., et al. (2014). Emerging roles of extracellular vesicles in the nervous system. J. Neurosci. 34, 15482-15489.
213. Recasens, A., Dehay, B., Bove, J., Carballo-Carbajal, I., Dovero, S., Perez-Villalba, A., Fernagut, P.O., Blesa, J., Parent, A., Perier, C., et al. (2014). Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. 75, 351-362.
214. Reyes, J.F., Rey, N.L., Bousset, L., Melki, R., Brundin, P., and Angot, E. (2014). Alpha-Synuclein transfers from neurons to oligodendrocytes. Glia 62, 387-398.
215. Rideout, H.J., Dietrich, P., Wang, Q., Dauer, W.T., and Stefanis, L. (2004). Alpha-Synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J. Biol. Chem. 279, 46915-46920.
216. Ronzitti, G., Bucci, G., Emanuele, M., Leo, D., Sotnikova, T.D., Mus, L.V., Soubrane, C.H., Dallas, M.L., Thalhammer, A., Cingolani, L.A., et al. (2014). Exogenous α-synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release. J. Neurosci. 34, 10603-10615.
217. Rostovtseva, T.K., Gurnev, P.A., Protchenko, O., Hoogerheide, D.P., Yap, T.L., Philpott, C.C., Lee, J.C., and Bezrukov, S.M. (2015). Alpha-Synuclein shows high affinity interaction with voltagedependent anion channel, suggesting mechanisms of mitochondrial regulation and toxicity in Parkinson disease. J. Biol. Chem. 290, 18467-18477.
218. Rott, R., Szargel, R., Haskin, J., Shani, V., Shainskaya, A., Manov, I., Liani, E., Avraham, E., and Engelender, S. (2008). Monoubiquitylation of α-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. J. Biol. Chem. 283, 3316-3328.
219. Rott, R., Szargel, R., Shani, V., Bisharat, S., and Engelender, S. (2014). Alpha-Synuclein ubiquitination and novel therapeutic targets for Parkinson's disease. CNS Neurol. Disord. Drug. Targets 13, 630-637.
220. Roy, S. (2009). The paradoxical cell biology of α-Synucle. Results Probl. Cell Differ. 48, 159-172.
221. Rutherford, N.J. and Giasson, B.I. (2015). The A53E α-synuclein pathological mutation demonstrates reduced aggregation propensity in vitro and in cell culture. Neurosci. Lett. 597, 43-48.
222. Sacino, A.N., Brooks, M., Thomas, M.A., McKinney, A.B., Lee, S., Regenhardt, R.W., McGarvey, N.H., Ayers, J.I., Notterpek, L., Borchelt, D.R., et al. (2014). Intramuscular injection of alphasynuclein induces CNS α-synuclein pathology and a rapidonset motor phenotype in transgenic mice. Proc. Natl. Acad. Sci. USA 111, 10732-10737.
223. Sadowski, M. and Sarcevic, B. (2010). Mechanisms of mono- and poly-ubiquitination: Ubiquitination specificity depends on compatibility between the E2 catalytic core and amino acid residues proximal to the lysine. Cell Div. 5, 19.
224. Sato, H., Kato, T., and Arawaka, S. (2013). The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson's disease: a review of in vivo models. Rev. Neurosci. 24, 115-123.
225. Schmidt, F., Levin, J., Kamp, F., Kretzschmar, H., Giese, A., and Botzel, K. (2012). Single-channel electrophysiology reveals a distinct and uniform pore complex formed by α-synuclein oligomers in lipid membranes. PLoS One 7, e42545.
226. Schneider, A. and Simons, M. (2013). Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res. 352, 33-47.
227. Shahpasandzadeh, H., Popova, B., Kleinknecht, A., Fraser, P.E., Outeiro, T.F., and Braus, G.H. (2014). Interplay between sumoylation and phosphorylation for protection against α-synuclein inclusions. J. Biol. Chem. 289, 31224-31240.
228. Shavali, S., Brown-Borg, H.M., Ebadi, M., and Porter, J. (2008). Mitochondrial localization of α-synuclein protein in α-synuclein overexpressing cells. Neurosci. Lett. 439, 125-128.
229. Shen, J., Du, T., Wang, X., Duan, C., Gao, G., Zhang, J., Lu, L., and Yang, H. (2014). Alpha-Synuclein amino terminus regulates mitochondrial membrane permeability. Brain Res. 1591, 14-26.
230. Sherer, T.B., and Greenamyre, J.T. (2005). Oxidative damage in Parkinson's disease. Antioxid. Redox. Signal 7, 627-629.
231. Shi, M., Liu, C., Cook, T.J., Bullock, K.M., Zhao, Y., Ginghina, C., Li, Y., Aro, P., Dator, R., He, C., et al. (2014). Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol. 128, 639-650.
232. Shimura, H., Schlossmacher, M.G., Hattori, N., Frosch, M.P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K.S., and Selkoe, D.J. (2001). Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293, 263-269.
233. Shin, Y., Klucken, J., Patterson, C., Hyman, B.T., and McLean, P.J. (2005). The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates α-synuclein degradation decisions between proteasomal and lysosomal pathways. J. Biol. Chem. 280, 23727-23734.
234. Shrivastava, A.N., Redeker, V., Fritz, N., Pieri, L., Almeida, L.G., Spolidoro, M., Liebmann, T., Bousset, L., Renner, M., Lena, C., et al. (2015). Alpha-Synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+gradient. EMBO J. 34, 2408-2423.
235. Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., et al. (2003). Alpha-Synuclein locus triplication causes Parkinson's disease. Science 302, 841.
236. Smith, W.W., Jiang, H., Pei, Z., Tanaka, Y., Morita, H., Sawa, A., Dawson, V.L., Dawson, T.M., and Ross, C.A. (2005a). Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant α-synuclein-induced toxicity. Hum. Mol. Genet. 14, 3801-3811.
237. Smith, W.W., Margolis, R.L., Li, X., Troncoso, J.C., Lee, M.K., Dawson, V.L., Dawson, T.M., Iwatsubo, T., and Ross, C.A. (2005b). Alpha-Synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J. Neurosci. 25, 5544-5552.
238. Snyder, H., Mensah, K., Theisler, C., Lee, J., Matouschek, A., and Wolozin, B. (2003). Aggregated and monomeric α-synuclein bind to the S6' proteasomal protein and inhibit proteasomal function. J. Biol. Chem. 278, 11753-11759.
239. Soper, J.H., Roy, S., Stieber, A., Lee, E., Wilson, R.B., Trojanowski, J.Q., Burd, C.G., and Lee, V.M. (2008). Alpha-Synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae. Mol. Biol. Cell 19, 1093-1103.
240. Souza, J.M., Giasson, B.I., Chen, Q., Lee, V.M., and Ischiropoulos, H. (2000). Dityrosine cross-linking promotes formation of stable α-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 275, 18344-18349.
241. Spencer, B., Potkar, R., Trejo, M., Rockenstein, E., Patrick, C., Gindi, R., Adame, A., Wyss-Coray, T., and Masliah, E. (2009). Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in α-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29, 13578-13588.
242. Spira, P.J., Sharpe, D.M., Halliday, G., Cavanagh, J., and Nicholson, G.A. (2001). Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr α-synuclein mutation. Ann. Neurol. 49, 313-319.
243. Stefanis, L., Larsen, K.E., Rideout, H.J., Sulzer, D., and Greene, L.A. (2001). Expression of A53T mutant but not wild-type α-synuclein in PC12 cells induces alterations of the ubiquitindependent degradation system, loss of dopamine release, and autophagic cell death. J. Neurosci. 21, 9549-9560.
244. Stockl, M.T., Zijlstra, N., and Subramaniam, V. (2013). Alpha-Synuclein oligomers: an amyloid pore? Insights into mechanisms of α-synuclein oligomer-lipid interactions. Mol. Neurobiol. 47, 613-621.
245. Stoica, R., De Vos, K.J., Paillusson, S., Mueller, S., Sancho, R.M., Lau, K.F., Vizcay-Barrena, G., Lin, W.L., Xu, Y.F., Lewis, J., et al. (2014). ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat. Commun. 5, 3996.
246. Stojkovska, I., Wagner, B.M., and Morrison, B.E. (2015). Parkinson's disease and enhanced inflammatory response. Exp. Biol. Med. (Maywood) 240, 1387-1395.
247. Street, J.M., Barran, P.E., Mackay, C.L., Weidt, S., Balmforth, C., Walsh, T.S., Chalmers, R.T., Webb, D.J., and Dear, J.W. (2012). Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J. Transl. Med. 10, 5.
248. Sugeno, N., Takeda, A., Hasegawa, T., Kobayashi, M., Kikuchi, A., Mori, F., Wakabayashi, K., and Itoyama, Y. (2008). Serine 129 phosphorylation of α-synuclein induces unfolded protein response-mediated cell death. J. Biol. Chem. 283, 23179-23188.
249. Tanaka, Y., Engelender, S., Igarashi, S., Rao, R.K., Wanner, T., Tanzi, R.E., Sawa, A., V, L.D., Dawson, T.M., and Ross, C.A. (2001). Inducible expression of mutant α-synuclein decreases proteasome activity and increases sensitivity to mitochondriadependent apoptosis. Hum. Mol. Genet. 10, 919-926.
250. Tenreiro, S., Eckermann, K., and Outeiro, T.F. (2014). Protein phosphorylation in neurodegeneration: friend or foe? Front. Mol. Neurosci. 7, 42.
251. Tetzlaff, J.E., Putcha, P., Outeiro, T.F., Ivanov, A., Berezovska, O., Hyman, B.T., and McLean, P.J. (2008). CHIP targets toxic α-synuclein oligomers for degradation. J. Biol. Chem. 283, 17962-17968.
252. Thayanidhi, N., Helm, J.R., Nycz, D.C., Bentley, M., Liang, Y., and Hay, J.C. (2010). Alpha-Synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/ Golgi SNAREs. Mol. Biol. Cell 21, 1850-1863.
253. Tofaris, G.K., Layfield, R., and Spillantini, M.G. (2001). Alpha- Synuclein metabolism and aggregation is linked to ubiquitinindependent degradation by the proteasome. FEBS Lett. 509, 22-26.
254. Tofaris, G.K., Razzaq, A., Ghetti, B., Lilley, K.S., and Spillantini, M.G. (2003). Ubiquitination of α-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J. Biol. Chem. 278, 44405-44411.
255. Tofaris, G.K., Kim, H.T., Hourez, R., Jung, J.W., Kim, K.P., and Goldberg, A.L. (2011). Ubiquitin ligase Nedd4 promotes α-synuclein degradation by the endosomal-lysosomal pathway. Proc. Natl. Acad. Sci. USA 108, 17004-17009.
256. Tosatto, L., Andrighetti, A.O., Plotegher, N., Antonini, V., Tessari, I., Ricci, L., Bubacco, L., and Dalla Serra, M. (2012). Alpha- Synuclein pore forming activity upon membrane association. Biochim. Biophys. Acta 1818, 2876-2883.
257. Tsigelny, I.F., Bar-On, P., Sharikov, Y., Crews, L., Hashimoto, M., Miller, M.A., Keller, S.H., Platoshyn, O., Yuan, J.X., and Masliah, E. (2007). Dynamics of α-synuclein aggregation and inhibition of pore-like oligomer development by β-synuclein. FEBS J. 274, 1862-1877.
258. Tsigelny, I.F., Sharikov, Y., Wrasidlo, W., Gonzalez, T., Desplats, P.A., Crews, L., Spencer, B., and Masliah, E. (2012). Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. FEBS J. 279, 1000-1013.
259. Tu, P.H., Galvin, J.E., Baba, M., Giasson, B., Tomita, T., Leight, S., Nakajo, S., Iwatsubo, T., Trojanowski, J.Q., and Lee, V.M. (1998). Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann. Neurol. 44, 415-422.
260. Ubeda-Banon, I., Saiz-Sanchez, D., de la Rosa-Prieto, C., and Martinez-Marcos, A. (2014). Alpha-Synuclein in the olfactory system in Parkinson's disease: role of neural connections on spreading pathology. Brain Struct. Funct. 219, 1513-1526.
261. Ueda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D.A., Kondo, J., Ihara, Y., and Saitoh, T. (1993). Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 11282-11286.
262. Ulusoy, A., Musgrove, R.E., Rusconi, R., Klinkenberg, M., Helwig, M., Schneider, A., and Di Monte, D.A. (2015). Neuron-to-neuron α-synuclein propagation in vivo is independent of neuronal injury. Acta Neuropathol. Commun. 3, 13.
263. Utton, M.A., Noble, W.J., Hill, J.E., Anderton, B.H., and Hanger, D.P. (2005). Molecular motors implicated in the axonal transport of tau and α-synuclein. J. Cell Sci. 118, 4645-4654.
264. Uversky, V.N., Li, J., and Fink, A.L. (2001). Evidence for a partially folded intermediate in α-synuclein fibril formation. J. Biol. Chem. 276, 10737-10744.
265. Valera, E., and Masliah, E. (2016). Combination therapies: the next logical Step for the treatment of synucleinopathies? Mov. Disord. 31, 225-234.
266. Vogiatzi, T., Xilouri, M., Vekrellis, K., and Stefanis, L. (2008). Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283, 23542-23556.
267. Wagner, J., Ryazanov, S., Leonov, A., Levin, J., Shi, S., Schmidt, F., Prix, C., Pan-Montojo, F., Bertsch, U., Mitteregger-Kretzschmar, G., et al. (2013). Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 125, 795-813.
268. Walker, D.G., Lue, L.F., Adler, C.H., Shill, H.A., Caviness, J.N., Sabbagh, M.N., Akiyama, H., Serrano, G.E., Sue, L.I., and Beach, T.G. (2013). Changes in properties of serine 129 phosphorylated α-synuclein with progression of Lewy-type histopathology in human brains. Exp. Neurol. 240, 190-204.
269. Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L.T., Liao, J., Auclair, J.R., Johnson, D., Landeru, A., Simorellis, A.K., et al. (2011). A soluble α-synuclein construct forms a dynamic tetramer. Proc. Natl. Acad. Sci. USA 108, 17797-17802.
270. Waxman, E.A. and Giasson, B.I. (2011). Induction of intracellular tau aggregation is promoted by α-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J. Neurosci. 31, 7604-7618.
271. Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N., and Rubinsztein, D.C. (2003). Alpha-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009-25013.
272. Weetman, J., Wong, M.B., Sharry, S., Rcom-H'cheo-Gauthier, A., Gai, W.P., Meedeniya, A., and Pountney, D.L. (2013). Increased SUMO-1 expression in the unilateral rotenone-lesioned mouse model of Parkinson's disease. Neurosci. Lett. 544, 119-124.
273. Winner, B., Jappelli, R., Maji, S.K., Desplats, P.A., Boyer, L., Aigner, S., Hetzer, C., Loher, T., Vilar, M., Campioni, S., et al. (2011). In vivo demonstration that α-synuclein oligomers are toxic. Proc. Natl. Acad. Sci. USA 108, 4194-4199.
274. 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. (2010). Alpha-Synuclein impairs macroautophagy: implications for Parkinson's disease. J. Cell Biol. 190, 1023-1037.
275. Wong, M.B., Goodwin, J., Norazit, A., Meedeniya, A.C., Richter- Landsberg, C., Gai, W.P., and Pountney, D.L. (2013). SUMO-1 is associated with a subset of lysosomes in glial protein aggregate diseases. Neurotox. Res. 23, 1-21.
276. Wood, S.J., Wypych, J., Steavenson, S., Louis, J.C., Citron, M., and Biere, A.L. (1999). Alpha-Synuclein fibrillogenesis is nucleation- dependent. Implications for the pathogenesis of Parkinson's disease. J. Biol. Chem. 274, 19509-19512.
277. Woods, W.S., Boettcher, J.M., Zhou, D.H., Kloepper, K.D., Hartman, K.L., Ladror, D.T., Qi, Z., Rienstra, C.M., and George, J.M. (2007). Conformation-specific binding of α-synuclein to novel protein partners detected by phage display and NMR spectroscopy. J. Biol. Chem. 282, 34555-34567.
278. Xilouri, M., Vogiatzi, T., Vekrellis, K., Park, D., and Stefanis, L. (2009). Abberant α-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 4, e5515.
279. Xin, W., Emadi, S., Williams, S., Liu, Q., Schulz, P., He, P., Alam, N.B., Wu, J., and Sierks, M.R. (2015). Toxic oligomeric α-synuclein variants present in human parkinson's disease brains are differentially generated in mammalian cell models. Biomolecules 5, 1634-1651.
280. Yamin, G., Uversky, V.N., and Fink, A.L. (2003). Nitration inhibits fibrillation of human α-synuclein in vitro by formation of soluble oligomers. FEBS Lett. 542, 147-152.
281. Yang, F., Yang, Y.P., Mao, C.J., Liu, L., Zheng, H.F., Hu, L.F., and Liu, C.F. (2013). Crosstalk between the proteasome system and autophagy in the clearance of α-synuclein. Acta Pharmacol. Sin. 34, 674-680.
282. Yonetani, M., Nonaka, T., Masuda, M., Inukai, Y., Oikawa, T., Hisanaga, S., and Hasegawa, M. (2009). Conversion of wildtype α-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant. J. Biol. Chem. 284, 7940-7950.
283. Yu, W.H., Dorado, B., Figueroa, H.Y., Wang, L., Planel, E., Cookson, M.R., Clark, L.N., and Duff, K.E. (2009). Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric α-synuclein. Am. J. Pathol. 175, 736-747.
284. Yu, Z., Xu, X., Xiang, Z., Zhou, J., Zhang, Z., Hu, C., and He, C. (2010). Nitrated α-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats. PLoS One 5, e9956.
285. Zakharov, S.D., Hulleman, J.D., Dutseva, E.A., Antonenko, Y.N., Rochet, J.C., and Cramer, W.A. (2007). Helical α-synuclein forms highly conductive ion channels. Biochemistry 46, 14369-14379.
286. Zampese, E., Fasolato, C., Kipanyula, M.J., Bortolozzi, M., Pozzan, T., and Pizzo, P. (2011). Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+cross-talk. Proc. Natl. Acad. Sci. USA 108, 2777-2782.
287. 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. (2004). The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164-173.
288. Zhang, S., Xie, J., Xia, Y., Yu, S., Gu, Z., Feng, R., Luo, G., Wang, D., Wang, K., Jiang, M., et al. (2015). LK6/Mnk2a is a new kinase of α-synuclein phosphorylation mediating neurodegeneration. Sci. Rep. 5, 12564.
289. Zuchner, T. and Brundin, P. (2008). Mutant huntingtin can paradoxically protect neurons from death. Cell Death Differ. 15, 435-442.