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CSPα knockout causes neurodegeneration by impairing SNAP‐25 function
Author(s) -
Sharma Manu,
Burré Jacqueline,
Bronk Peter,
Zhang Yingsha,
Xu Wei,
Südhof Thomas C
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.467
Subject(s) - medical genetics , biology , library science , genetics , computer science , gene
At a synapse, the synaptic vesicle protein cysteine‐string protein‐α (CSPα) functions as a co‐chaperone for the SNARE protein SNAP‐25. Knockout (KO) of CSPα causes fulminant neurodegeneration that is rescued by α‐synuclein overexpression. The CSPα KO decreases SNAP‐25 levels and impairs SNARE‐complex assembly; only the latter but not the former is reversed by α‐synuclein. Thus, the question arises whether the CSPα KO phenotype is due to decreased SNAP‐25 function that then causes neurodegeneration, or due to the dysfunction of multiple as‐yet uncharacterized CSPα targets. Here, we demonstrate that decreasing SNAP‐25 levels in CSPα KO mice by either KO or knockdown of SNAP‐25 aggravated their phenotype. Conversely, increasing SNAP‐25 levels by overexpression rescued their phenotype. Inactive SNAP‐25 mutants were unable to rescue, showing that the rescue was specific. Under all conditions, the neurodegenerative phenotype precisely correlated with SNARE‐complex assembly, indicating that impaired SNARE‐complex assembly due to decreased SNAP‐25 levels is the ultimate correlate of neurodegeneration. Our findings suggest that the neurodegeneration in CSPα KO mice is primarily produced by defective SNAP‐25 function, which causes neurodegeneration by impairing SNARE‐complex assembly.