title: CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity.
abstract: A neuron forms thousands of presynaptic nerve terminals on its axons, far removed from the cell body. The protein CSPα resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT. Deletion of CSPα results in massive neurodegeneration that impairs survival in mice and flies. In CSPα-knockout mice, levels of presynaptic SNARE complexes and the SNARE protein SNAP-25 are reduced, suggesting that CSPα may chaperone SNARE proteins, which catalyse synaptic vesicle fusion. Here, we show that the CSPα-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation. Deletion of CSPα produces an abnormal SNAP-25 conformer that inhibits SNARE-complex formation, and is subject to ubiquitylation and proteasomal degradation. Even in wild-type mouse terminals, SNAP-25 degradation is regulated by synaptic activity; this degradation is decreased by CSPα overexpression, and enhanced by CSPα deletion. Thus, SNAP-25 function is maintained during rapid SNARE cycles by equilibrium between CSPα-dependent chaperoning and ubiquitin-dependent degradation, revealing unique protein quality-control machinery within the presynaptic compartment.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, SIM1, 265 Campus Drive, Palo Alto, CA 94304-5453, USA. sharma11@stanford.edu
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Burré
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050600:SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; C494372:Hspa8 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones; D050600:SNARE Proteins; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D051844:alpha-Synuclein; C088460:cysteine string protein; D046988:Proteasome Endopeptidase Complex