title: Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.
abstract: Presynaptic nerve terminals release neurotransmitters repeatedly, often at high frequency, and in relative isolation from neuronal cell bodies. Repeated release requires cycles of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly and disassembly, with continuous generation of reactive SNARE-protein intermediates. Although many forms of neurodegeneration initiate presynaptically, only few pathogenic mechanisms are known, and the functions of presynaptic proteins linked to neurodegeneration, such as α-synuclein, remain unclear. Here, we show that maintenance of continuous presynaptic SNARE-complex assembly required a nonclassical chaperone activity mediated by synucleins. Specifically, α-synuclein directly bound to the SNARE-protein synaptobrevin-2/vesicle-associated membrane protein 2 (VAMP2) and promoted SNARE-complex assembly. Moreover, triple-knockout mice lacking synucleins developed age-dependent neurological impairments, exhibited decreased SNARE-complex assembly, and died prematurely. Thus, synucleins may function to sustain normal SNARE-complex assembly in a presynaptic terminal during aging.
authors.affiliation: Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Burré
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Theodoros
authors.initials: T
authors.lastname: Tsetsenis
authors.forename: Vladimir
authors.initials: V
authors.lastname: Buchman
authors.forename: Mark R
authors.initials: MR
authors.lastname: Etherton
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000375:Aging; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D050600:SNARE Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein; C088460:cysteine string protein; C494808:vesicle-associated membrane protein 2, mouse
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