| First Author | Sharma M | Year | 2011 |
| Journal | Nat Cell Biol | Volume | 13 |
| Issue | 1 | Pages | 30-9 |
| PubMed ID | 21151134 | Mgi Jnum | J:169031 |
| Mgi Id | MGI:4939561 | Doi | 10.1038/ncb2131 |
| Citation | Sharma M, et al. (2011) CSPalpha promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. Nat Cell Biol 13(1):30-9 |
| abstractText | A neuron forms thousands of presynaptic nerve terminals on its axons, far removed from the cell body. The protein CSPalpha resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT. Deletion of CSPalpha results in massive neurodegeneration that impairs survival in mice and flies. In CSPalpha-knockout mice, levels of presynaptic SNARE complexes and the SNARE protein SNAP-25 are reduced, suggesting that CSPalpha may chaperone SNARE proteins, which catalyse synaptic vesicle fusion. Here, we show that the CSPalpha-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation. Deletion of CSPalpha 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 CSPalpha overexpression, and enhanced by CSPalpha deletion. Thus, SNAP-25 function is maintained during rapid SNARE cycles by equilibrium between CSPalpha-dependent chaperoning and ubiquitin-dependent degradation, revealing unique protein quality-control machinery within the presynaptic compartment. |
