Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.
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.
Burré
Jacqueline
J
Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.
Sharma
Manu
M
Tsetsenis
Theodoros
T
Buchman
Vladimir
V
Etherton
Mark R
MR
Südhof
Thomas C
TC
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*
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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