CSPα knockout causes neurodegeneration by impairing SNAP-25 function

At a synapse, the synaptic vesicle protein cysteine-string protein-alpha (CSP alpha) functions as a co-chaperone for the SNARE protein SNAP-25. Knockout (KO) of CSP alpha causes fulminant neurodegeneration that is rescued by alpha-synuclein overexpression. The CSP alpha KO decreases SNAP-25 levels and impairs SNARE-complex assembly; only the latter but not the former is reversed by alpha-synuclein. Thus, the question arises whether the CSP alpha KO phenotype is due to decreased SNAP-25 function that then causes neurodegeneration, or due to the dysfunction of multiple as-yet uncharacterized CSP alpha targets. Here, we demonstrate that decreasing SNAP-25 levels in CSP alpha 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 alpha KO mice is primarily produced by defective SNAP-25 function, which causes neurodegeneration by impairing SNARE-complex assembly. The EMBO Journal (2012) 31, 829-841. doi: 10.1038/emboj.2011.467; Published online 20 December 2011