Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.

TitleAlpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.
Publication TypeJournal Article
Year of Publication2010
AuthorsBurré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC
JournalScience
Volume329
Issue5999
Pagination1663-7
Date Published2010 Sep 24
ISSN1095-9203
KeywordsAging, alpha-Synuclein, Animals, Cell Line, Cells, Cultured, HSP40 Heat-Shock Proteins, Humans, Membrane Fusion, Membrane Proteins, Mice, Mice, Knockout, Mice, Transgenic, Nerve Degeneration, Neurons, Presynaptic Terminals, Protein Binding, Rats, Recombinant Fusion Proteins, SNARE Proteins, Vesicle-Associated Membrane Protein 2
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.

DOI10.1126/science.1195227
Alternate JournalScience
PubMed ID20798282
PubMed Central IDPMC3235365
Grant List / / Howard Hughes Medical Institute / United States
075615 / / Wellcome Trust / United Kingdom