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Science 329 (5999): 1663-1667

Copyright © 2010 by the American Association for the Advancement of Science

{alpha}-Synuclein Promotes SNARE-Complex Assembly in Vivo and in Vitro

Jacqueline Burré,1,* Manu Sharma,1,* Theodoros Tsetsenis,1 Vladimir Buchman,2 Mark R. Etherton,1 Thomas C. Südhof1,3,{dagger}

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 {alpha}-synuclein, remain unclear. Here, we show that maintenance of continuous presynaptic SNARE-complex assembly required a nonclassical chaperone activity mediated by synucleins. Specifically, {alpha}-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.

1 Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304–5543, USA.
2 School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
3 Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304–5543, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: tcs1{at}stanford.edu


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