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 journalArticle

86 Citations (Scopus)

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

Fingerprint

SNARE Proteins
Synucleins
Phenotype
Knockout Mice
Synaptic Vesicles
cysteine string protein
Synapses
Proteins

Keywords

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

ASJC Scopus subject areas

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

Cite this

Sharma, M., Burré, J., Bronk, P., Zhang, Y., Xu, W., & Südhof, T. C. (2012). CSPα knockout causes neurodegeneration by impairing SNAP-25 function. EMBO Journal, 31(4), 829-841. https://doi.org/10.1038/emboj.2011.467

CSPα knockout causes neurodegeneration by impairing SNAP-25 function. / Sharma, Manu; Burré, Jacqueline; Bronk, Peter; Zhang, Yingsha; Xu, Wei; Südhof, Thomas C.

In: EMBO Journal, Vol. 31, No. 4, 15.02.2012, p. 829-841.

Research output: Contribution to journalArticle

Sharma, M, Burré, J, Bronk, P, Zhang, Y, Xu, W & Südhof, TC 2012, 'CSPα knockout causes neurodegeneration by impairing SNAP-25 function', EMBO Journal, vol. 31, no. 4, pp. 829-841. https://doi.org/10.1038/emboj.2011.467
Sharma, Manu ; Burré, Jacqueline ; Bronk, Peter ; Zhang, Yingsha ; Xu, Wei ; Südhof, Thomas C. / CSPα knockout causes neurodegeneration by impairing SNAP-25 function. In: EMBO Journal. 2012 ; Vol. 31, No. 4. pp. 829-841.
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