New insights into cellular α-synuclein homeostasis in health and disease

Current Opinion in Neurobiology

Volumn 36, Issue , 2016, Pages 15-22

  Dettmer, Ulf ^a   Selkoe, Dennis ^a   Bartels, Tim ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; MONOMER; OLIGOMER;

BINDING AFFINITY; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN ASSEMBLY; PROTEIN CONFORMATION; PROTEIN INTERACTION; PROTEIN LOCALIZATION; PROTEIN METABOLISM; PROTEIN MULTIMERIZATION; REVIEW; BRAIN; CELL MEMBRANE; DEGENERATIVE DISEASE; DIFFUSE LEWY BODY DISEASE; HOMEOSTASIS; METABOLISM; NERVE CELL; PARKINSON DISEASE;

ALPHA-SYNUCLEIN; BRAIN; CELL MEMBRANE; HOMEOSTASIS; HUMANS; LEWY BODY DISEASE; NEURODEGENERATIVE DISEASES; NEURONS; PARKINSON DISEASE; PROTEIN MULTIMERIZATION;

EID: 84941313512     PISSN: 09594388     EISSN: 18736882     Source Type: Journal    
DOI: 10.1016/j.conb.2015.07.007     Document Type: Review

References (78)

1. Weinreb P.H., Zhen W., Poon A.W., Conway K.A., Lansbury P.T. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 1996, 35:13709-13715.
2. 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.
3. Bousset L., Pieri L., Ruiz-Arlandis G., Gath J., Jensen P.H., Habenstein B., Madiona K., Olieric V., Böckmann A., Meier B.H., et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun 2013, 4:2575.
4. Peelaerts W., Bousset L., Van der Perren A., Moskalyuk A., Pulizzi R., Giugliano M., Van den Haute C., Melki R., Baekelandt V. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 2015, 522:340-344.
5. Foguel D., Suarez M.C., Ferrão-Gonzales A.D., Porto T.C.R., Palmieri L., Einsiedler C.M., Andrade L.R., Lashuel H.A., Lansbury P.T., Kelly J.W., et al. Dissociation of amyloid fibrils of alpha-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavities. Proc Natl Acad Sci U S A 2003, 100:9831-9836.
6. Quintas A., Saraiva M.J., Brito R.M. The tetrameric protein transthyretin dissociates to a non-native monomer in solution. A novel model for amyloidogenesis. J Biol Chem 1999, 274:32943-32949.
7. Bartels T., Choi J.G., Selkoe D.J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011, 477:107-110.
8. Wang W., Perovic I., Chittuluru J., Kaganovich A., Nguyen L.T.T., Liao J., Auclair J.R., Johnson D., Landeru A., Simorellis A.K., et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A 2011, 108:17797-17802.
9. Maroteaux L., Scheller R.H. The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Brain Res Mol Brain Res 1991, 11:335-343.
10. Cole N.B., Murphy D.D., Grider T., Rueter S., Brasaemle D., Nussbaum R.L. Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein. J Biol Chem 2002, 277:6344-6352.
11. Klucken J., Outeiro T.F., Nguyen P., McLean P.J., Hyman B.T. Detection of novel intracellular alpha-synuclein oligomeric species by fluorescence lifetime imaging. FASEB J 2006, 20:2050-2057.
12. Dettmer U., Newman A.J., Luth E.S., Bartels T., Selkoe D. In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. J Biol Chem 2013, 288:6371-6385.
13. 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. α-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem 2012, 287:15345-15364.
14. Binolfi A., Theillet F.-X., Selenko P. Bacterial in-cell NMR of human α-synuclein: a disordered monomer by nature?. Biochem Soc Trans 2012, 40:950-954.
15. Burré J., Vivona S., Diao J., Sharma M., Brunger A.T., Südhof T.C. Properties of native brain α-synuclein. Nature 2013, 498:E4-E6. discussion E6-7.
16. Westphal C.H., Chandra S.S. Monomeric synucleins generate membrane curvature. J Biol Chem 2013, 288:1829-1840.
17. Gould N., Mor D.E., Lightfoot R., Malkus K., Giasson B., Ischiropoulos H. Evidence of native α-synuclein conformers in the human brain. J Biol Chem 2014, 289:7929-7934.
18. Trexler A.J., Rhoades E. N-terminal acetylation is critical for forming α-helical oligomer of α-synuclein. Protein Sci 2012, 21:601-605.
19. Burré J., Sharma M., Südhof T.C. α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci U S A 2014, 111:E4274-E4283.
20. Burré J., Sharma M., Südhof T.C. Definition of a molecular pathway mediating α-synuclein neurotoxicity. J Neurosci Off J Soc Neurosci 2015, 35:5221-5232.
21. Bartels T., Kim N.C., Luth E.S., Selkoe D.J. N-alpha-acetylation of α-synuclein increases its helical folding propensity, GM1 binding specificity and resistance to aggregation. PlOS ONE 2014, 9:e103727.
22. Luth E.S., Bartels T., Dettmer U., Kim N.C., Selkoe D.J. Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity. Biochemistry 2015, 54:279-292.
23. Gurry T., Ullman O., Fisher C.K., Perovic I., Pochapsky T., Stultz C.M. The dynamic structure of α-synuclein multimers. J Am Chem Soc 2013, 135:3865-3872.
24. Fonseca-Ornelas L., Eisbach S.E., Paulat M., Giller K., Fernández C.O., Outeiro T.F., Becker S., Zweckstetter M. Small molecule-mediated stabilization of vesicle-associated helical α-synuclein inhibits pathogenic misfolding and aggregation. Nat. Commun. 2014, 5:5857.
25. 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.
26. Krüger R., Kuhn W., Müller T., Woitalla D., Graeber M., Kösel S., Przuntek H., Epplen J.T., Schöls L., Riess O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998, 18:106-108.
27. Zarranz J.J., Alegre J., Gómez-Esteban J.C., Lezcano E., Ros R., Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atarés B., et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004, 55:164-173.
28. 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.
29. Proukakis C., Dudzik C.G., Brier T., MacKay D.S., Cooper J.M., Millhauser G.L., Houlden H., Schapira A.H. A novel α-synuclein missense mutation in Parkinson disease. Neurology 2013, 80:1062-1064.
30. Kara E., Lewis P.A., Ling H., Proukakis C., Houlden H., Hardy J. α-Synuclein mutations cluster around a putative protein loop. Neurosci Lett 2013, 546:67-70.
31. Dettmer U., Newman A.J., Soldner F., Luth E.S., Kim N.C., von Saucken V.E., Sanderson J.B., Jaenisch R., Bartels T., Selkoe D. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun 2015, 6:7314.
32. Conway K.A., Harper J.D., Lansbury P.T. Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry 2000, 39:2552-2563.
33. Greenbaum E.A., Graves C.L., Mishizen-Eberz A.J., Lupoli M.A., Lynch D.R., Englander S.W., Axelsen P.H., Giasson B.I. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 2005, 280:7800-7807.
34. 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. The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity. J Biol Chem 2014, 289:21856-21876.
35. Rutherford N.J., Moore B.D., Golde T.E., Giasson B.I. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein. J Neurochem 2014, 131:859-867.
36. 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, 302:841.
37. 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.
38. George J.M., Jin H., Woods W.S., Clayton D.F. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 1995, 15:361-372.
39. Irizarry M.C., Kim T.W., McNamara M., Tanzi R.E., George J.M., Clayton D.F., Hyman B.T. Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous system. J Neuropathol Exp Neurol 1996, 55:889-895.
40. Kahle P.J., Neumann M., Ozmen L., Müller V., Odoy S., Okamoto N., Jacobsen H., Iwatsubo T., Trojanowski J.Q., Takahashi H., et al. Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 2001, 159:2215-2225.
41. Fortin D.L., Troyer M.D., Nakamura K., Kubo S., Anthony M.D., Edwards R.H. Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci 2004, 24:6715-6723.
42. Nakajo S., Shioda S., Nakai Y., Nakaya K. Localization of phosphoneuroprotein 14 (PNP 14) and its mRNA expression in rat brain determined by immunocytochemistry and in situ hybridization. Brain Res Mol Brain Res 1994, 27:81-86.
43. Fortin D.L., Nemani V.M., Voglmaier S.M., Anthony M.D., Ryan T.A., Edwards R.H. Neural activity controls the synaptic accumulation of alpha-synuclein. J Neurosci 2005, 25:10913-10921.
44. Pranke I.M., Morello V., Bigay J., Gibson K., Verbavatz J.-M., Antonny B., Jackson C.L. α-Synuclein and ALPS motifs are membrane curvature sensors whose contrasting chemistry mediates selective vesicle binding. J Cell Biol 2011, 194:89-103.
45. Zarbiv Y., Simhi-Haham D., Israeli E., Elhadi S.A., Grigoletto J., Sharon R. Lysine residues at the first and second KTKEGV repeats mediate α-synuclein binding to membrane phospholipids. Neurobiol Dis 2014, 70:90-98.
46. Dettmer U., Newman A.J., Saucken, von V.E., Bartels T., Selkoe D. KTKEGV repeat motifs are key mediators of normal α-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity. PNAS 2015, 112:9596-9601.
47. Jensen P.H., Nielsen M.S., Jakes R., Dotti C.G., Goedert M. Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation. J Biol Chem 1998, 273:26292-26294.
48. Fares M.-B., Ait-Bouziad N., Dikiy I., Mbefo M.K., Jovičić A., Kiely A., Holton J.L., Lee S.-J., Gitler A.D., Eliezer D., et al. 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 2014, 23:4491-4509.
49. Wang L., Das U., Scott D.A., Tang Y., McLean P.J., Roy S. α-Synuclein multimers cluster synaptic vesicles and attenuate recycling. Curr Biol 2014, 24:2319-2326.
50. Golebiewska U., Zurawsky C., Scarlata S. Defining the oligomerization state of γ-synuclein in solution and in cells. Biochemistry 2014, 53:293-299.
51. Davidson W.S., Jonas A., Clayton D.F., George J.M. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 1998, 273:9443-9449.
52. Jao C.C., Hegde B.G., Chen J., Haworth I.S., Langen R. Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement. Proc Natl Acad Sci U S A 2008, 105:19666-19671.
53. Varkey J., Mizuno N., Hegde B.G., Cheng N., Steven A.C., Langen R. α-Synuclein oligomers with broken helical conformation form lipoprotein nanoparticles. J Biol Chem 2013, 288:17620-17630.
54. Wislet-Gendebien S., D'Souza C., Kawarai T., St George-Hyslop P., Westaway D., Fraser P., Tandon A. Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes. J Biol Chem 2006, 281:32148-32155.
55. Chen R.H.C., Wislet-Gendebien S., Samuel F., Visanji N.P., Zhang G., Marsilio D., Langman T., Fraser P.E., Tandon A. α-Synuclein membrane association is regulated by the Rab3a recycling machinery and presynaptic activity. J Biol Chem 2013, 288:7438-7449.
56. Abeliovich A., Schmitz Y., Fariñas 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.
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. Larsen K.E., Schmitz Y., Troyer M.D., Mosharov E., Dietrich P., Quazi A.Z., Savalle M., Nemani V., Chaudhry F.A., Edwards R.H., et al. Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci 2006, 26:11915-11922.
59. 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.
60. Vargas K.J., Makani S., Davis T., Westphal C.H., Castillo P.E., Chandra S.S. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci 2014, 34:9364-9376.
61. Kamp F., Exner N., Lutz A.K., Wender N., Hegermann J., Brunner B., Nuscher B., Bartels T., Giese A., Beyer K., et al. Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J 2010, 29:3571-3589.
62. Varkey J., Isas J.M., Mizuno N., Jensen M.B., Bhatia V.K., Jao C.C., Petrlova J., Voss J.C., Stamou D.G., Steven A.C., et al. Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. J Biol Chem 2010, 285:32486-32493.
63. DeWitt D.C., Rhoades E. α-Synuclein can inhibit SNARE-mediated vesicle fusion through direct interactions with lipid bilayers. Biochemistry 2013, 52:2385-2387.
64. Burré J., Sharma M., Tsetsenis T., Buchman V., Etherton M.R., Südhof T.C. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 329:1663-1667.
65. Ysselstein D., Joshi M., Mishra V., Griggs A.M., Asiago J.M., McCabe G.P., Stanciu L.A., Post C.B., Rochet J.-C. Effects of impaired membrane interactions on α-synuclein aggregation and neurotoxicity. Neurobiol Dis 2015, 79:150-163.
66. Galvagnion C., Buell A.K., Meisl G., Michaels T.C.T., Vendruscolo M., Knowles T.P.J., Dobson C.M. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat Chem Biol 2015, 11:229-234.
67. Volles M.J., Lansbury P.T. Relationships between the sequence of alpha-synuclein and its membrane affinity, fibrillization propensity, and yeast toxicity. J Mol Biol 2007, 366:1510-1522.
68. 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 alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A 2008, 105:145-150.
69. Tofaris G.K., Kim H.T., Hourez R., Jung J.-W., Kim K.P., Goldberg A.L. Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway. Proc Natl Acad Sci U S A 2011, 108:17004-17009.
70. Tardiff D.F., Jui N.T., Khurana V., Tambe M.A., Thompson M.L., Chung C.Y., Kamadurai H.B., Kim H.T., Lancaster A.K., Caldwell K.A., et al. Yeast reveal a druggable Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science 2013, 342:979-983.
71. 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. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 2013, 342:983-987.
72. Davies S.E., Hallett P.J., Moens T., Smith G., Mangano E., Kim H.T., Goldberg A.L., Liu J.-L., Isacson O., Tofaris G.K. Enhanced ubiquitin-dependent degradation by Nedd4 protects against α-synuclein accumulation and toxicity in animal models of Parkinson's disease. Neurobiol Dis 2014, 64:79-87.
73. Hansen C., Angot E., Bergström A.-L., Steiner J.A., Pieri L., Paul G., Outeiro T.F., Melki R., Kallunki P., Fog K., et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 2011, 121:715-725.
74. Volpicelli-Daley L.A., Luk K.C., Patel T.P., Tanik S.A., Riddle D.M., Stieber A., Meaney D.F., Trojanowski J.Q., Lee V.M.-Y. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011, 72:57-71.
75. Luk K.C., Kehm V.M., Zhang B., O'Brien P., Trojanowski J.Q., Lee V.M.Y. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 2012, 209:975-986.
76. Emmanouilidou E., Melachroinou K., Roumeliotis T., Garbis S.D., Ntzouni M., Margaritis L.H., Stefanis L., Vekrellis K. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 2010, 30:6838-6851.
77. Danzer K.M., Kranich L.R., Ruf W.P., Cagsal-Getkin O., Winslow A.R., Zhu L., Vanderburg C.R., McLean P.J. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 2012, 7:42.
78. Tsunemi T., Hamada K., Krainc D. ATP13A2/PARK9 regulates secretion of exosomes and α-synuclein. J Neurosci 2014, 34:15281-15287.