| First Author | Sharma M | Year | 2012 |
| Journal | EMBO J | Volume | 31 |
| Issue | 4 | Pages | 829-41 |
| PubMed ID | 22187053 | Mgi Jnum | J:181971 |
| Mgi Id | MGI:5314486 | Doi | 10.1038/emboj.2011.467 |
| Citation | Sharma M, et al. (2012) CSPalpha knockout causes neurodegeneration by impairing SNAP-25 function. EMBO J 31(4):829-41 |
| abstractText | At a synapse, the synaptic vesicle protein cysteine-string protein-alpha (CSPalpha) functions as a co-chaperone for the SNARE protein SNAP-25. Knockout (KO) of CSPalpha causes fulminant neurodegeneration that is rescued by alpha-synuclein overexpression. The CSPalpha 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 CSPalpha KO phenotype is due to decreased SNAP-25 function that then causes neurodegeneration, or due to the dysfunction of multiple as-yet uncharacterized CSPalpha targets. Here, we demonstrate that decreasing SNAP-25 levels in CSPalpha 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 CSPalpha KO mice is primarily produced by defective SNAP-25 function, which causes neurodegeneration by impairing SNARE-complex assembly. |
