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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


  • Sharma M
  • Burré J
  • Südhof TC


Nature cell biology

Publication Data

January 21, 2011

Associated Grants

  • Agency: NIA NIH HHS, Id: RC2AG036614
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • 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