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

• Published in: Nature cell biology Vol. 13; no. 1; pp. 30 - 39
• Main Authors: Sharma, Manu, Burré, Jacqueline, Südhof, Thomas C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2011; Nature Publishing Group
• Subjects: 631/45/612/1241; 631/80/313/2104; 631/80/474/1768; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; alpha-Synuclein - physiology; Animals; Animals, Newborn; Biomedical and Life Sciences; Brain - metabolism; Cancer Research; Cell Biology; Cells, Cultured; Developmental Biology; Female; HEK293 Cells; HSC70 Heat-Shock Proteins - metabolism; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; HSP40 Heat-Shock Proteins - physiology; Humans; Immunoblotting; Life Sciences; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Knockout; Mice, Transgenic; Molecular chaperones; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Neural transmission; Neurons; Neurons - cytology; Neurons - metabolism; Neurons - physiology; Physiological aspects; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Rats; Reverse Transcriptase Polymerase Chain Reaction; SNARE Proteins - genetics; SNARE Proteins - metabolism; Stem Cells; Synaptic Transmission - physiology; Synaptosomal-Associated Protein 25 - genetics; Synaptosomal-Associated Protein 25 - metabolism; Temperature; Ubiquitination; United States
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/ncb2131

A chaperone complex containing CSPα, Hsc70 and SGT binds to monomeric SNAP-25 and prevents its aggregation and degradation. Loss of CSPα inhibits SNARE complex formation. 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.