CSPα knockout causes neurodegeneration by impairing SNAP-25 function.

TitleCSPα knockout causes neurodegeneration by impairing SNAP-25 function.
Publication TypeJournal Article
Year of Publication2012
AuthorsSharma M, Burré J, Bronk P, Zhang Y, Xu W, Südhof TC
JournalEMBO J
Date Published2012 Feb 15
KeywordsAnimals, HSP40 Heat-Shock Proteins, Membrane Proteins, Mice, Mice, Knockout, Phenotype, Synaptic Transmission, Synaptosomal-Associated Protein 25

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.

Alternate JournalEMBO J.
PubMed ID22187053
PubMed Central IDPMC3280561
Grant ListRC2 AG036614 / AG / NIA NIH HHS / United States
RC2AG036614 / AG / NIA NIH HHS / United States