CSPα knockout causes neurodegeneration by impairing SNAP-25 function

Manu Sharma, Jacqueline Burré, Peter Bronk, Yingsha Zhang, Wei Xu, Thomas C. Südhof

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)829-841
Number of pages13
JournalEMBO Journal
Volume31
Issue number4
DOIs
StatePublished - Feb 15 2012

Keywords

  • CSPα
  • SNAP-25
  • SNARE complex
  • neurodegeneration
  • synapse

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint Dive into the research topics of 'CSPα knockout causes neurodegeneration by impairing SNAP-25 function'. Together they form a unique fingerprint.

Cite this