α-Synuclein promotes SNARE-complex assembly in vivo and in vitro

Burre, Jacqueline, Sharma, Manu, Tsetsenis, Theodoros, Buchman, Vladimir L. ORCID: https://orcid.org/0000-0002-7631-8352, Etherton, Mark R. and Sudhof, Thomas C. 2010. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329 (5999) , pp. 1663-1667. 10.1126/science.1195227

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > Q Science (General) Q Science > QH Natural history > QH301 Biology
Publisher:	AAAS
ISSN:	0036-8075
Last Modified:	19 Oct 2022 10:07
URI:	https://orca.cardiff.ac.uk/id/eprint/23328

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