CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity.
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.
Pubmed ID: 21151134 RIS Download
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 | alpha-Synuclein