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

Science (New York, N.Y.) | Sep 24, 2010

http://www.ncbi.nlm.nih.gov/pubmed/20798282

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.

Pubmed ID: 20798282 RIS Download

Mesh terms: Aging | 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 | alpha-Synuclein

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Associated grants

  • Agency: Wellcome Trust, Id: 075615
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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