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Nat Cell Biol. 2011 Jan;13(1):30-9. doi: 10.1038/ncb2131. Epub 2010 Dec 12.

CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University, SIM1, 265 Campus Drive, Palo Alto, CA 94304-5453, USA. sharma11@stanford.edu

Erratum in

  • Nat Cell Biol. 2011 Feb;13(2):182.

Abstract

A neuron forms thousands of presynaptic nerve terminals on its axons, far removed from the cell body. The protein CSPα resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT. Deletion of CSPα results in massive neurodegeneration that impairs survival in mice and flies. In CSPα-knockout mice, levels of presynaptic SNARE complexes and the SNARE protein SNAP-25 are reduced, suggesting that CSPα may chaperone SNARE proteins, which catalyse synaptic vesicle fusion. Here, we show that the CSPα-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation. Deletion of CSPα produces an abnormal SNAP-25 conformer that inhibits SNARE-complex formation, and is subject to ubiquitylation and proteasomal degradation. Even in wild-type mouse terminals, SNAP-25 degradation is regulated by synaptic activity; this degradation is decreased by CSPα overexpression, and enhanced by CSPα deletion. Thus, SNAP-25 function is maintained during rapid SNARE cycles by equilibrium between CSPα-dependent chaperoning and ubiquitin-dependent degradation, revealing unique protein quality-control machinery within the presynaptic compartment.

PMID:
21151134
DOI:
10.1038/ncb2131
[Indexed for MEDLINE]

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