CSP? knockout causes neurodegeneration by impairing SNAP-25 function.

ABSTRACT: At a synapse, the synaptic vesicle protein cysteine-string protein-? (CSP?) functions as a co-chaperone for the SNARE protein SNAP-25. Knockout (KO) of CSP? causes fulminant neurodegeneration that is rescued by ?-synuclein overexpression. The CSP? KO decreases SNAP-25 levels and impairs SNARE-complex assembly; only the latter but not the former is reversed by ?-synuclein. Thus, the question arises whether the CSP? KO phenotype is due to decreased SNAP-25 function that then causes neurodegeneration, or due to the dysfunction of multiple as-yet uncharacterized CSP? targets. Here, we demonstrate that decreasing SNAP-25 levels in CSP? 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 CSP? KO mice is primarily produced by defective SNAP-25 function, which causes neurodegeneration by impairing SNARE-complex assembly.

SUBMITTER: Sharma M 

PROVIDER: S-EPMC3280561 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature