title: CSPα knockout causes neurodegeneration by impairing SNAP-25 function.
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.
authors.affiliation: Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. sharma11@stanford.edu
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Burré
authors.forename: Peter
authors.initials: P
authors.lastname: Bronk
authors.forename: Yingsha
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D009435:Synaptic Transmission; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000502:physiology*
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; C088460:cysteine string protein