CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity.

TitleCSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity.
Publication TypeJournal Article
Year of Publication2011
AuthorsSharma M, Burré J, Südhof TC
JournalNat Cell Biol
Date Published2011 Jan
Keywordsalpha-Synuclein, Animals, Animals, Newborn, Brain, Cells, Cultured, Female, HEK293 Cells, HSC70 Heat-Shock Proteins, HSP40 Heat-Shock Proteins, Humans, Immunoblotting, Male, Membrane Proteins, Mice, Mice, Knockout, Mice, Transgenic, Molecular Chaperones, Neurons, Proteasome Endopeptidase Complex, Protein Binding, Rats, Reverse Transcriptase Polymerase Chain Reaction, SNARE Proteins, Synaptic Transmission, Synaptosomal-Associated Protein 25, Temperature, Ubiquitination

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.

Alternate JournalNat. Cell Biol.
PubMed ID21151134
Grant ListRC2AG036614 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States