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

Nature Cell Biology volume 13, pages 30–39 (2011)Cite this article

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A Corrigendum to this article was published on 01 February 2011

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Abstract

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.

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Figure 1: CSPα knockout selectively decreases SNAP-25 levels and increases SNAP-25 protease sensitivity.
Figure 2: CSPα deletion increases SNAP-25 ubiquitylation and proteasomal degradation.
Figure 3: Neuronal activity controls SNAP-25 levels in a CSPα-dependent manner.
Figure 4: CSPα overexpression stabilizes SNAP-25.
Figure 5: CSPα binds to monomeric SNAP-25 through Hsc70.
Figure 6: The CSPα–Hsc70–SGT complex chaperones SNAP-25 and enhances its incorporation into SNARE complexes in vitro.
Figure 7: Model of the function of the CSPα–Hsc70–SGT chaperone complex.

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  • 21 December 2010

    In the version of this article initially published online and in print, grant information was missing from the acknowledgements.

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Acknowledgements

We thank S. Chandra for discussions, and J. Mitchell, A. Roth and I. Kornblum for technical support. This work was supported by the National Institute on Aging (NIH grant RC2AG036614 to T.C.S.), and fellowships from the Human Frontiers Program (LT00527/2006-L to M.S.) and the 'Deutsche Akademie der Naturforscher Leopoldina' (BMBF-LPD 9901/8-161 to J.B.).

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Stanford University, SIM1, 265 Campus Drive, Palo Alto, 94304-5453, CA, USA

    Manu Sharma, Jacqueline Burré & Thomas C. Südhof

  2. Howard Hughes Medical Institute, Stanford University, SIM1, 265 Campus Drive, Palo Alto, 94304-5453, CA, USA

    Thomas C. Südhof

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  1. Manu Sharma
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  2. Jacqueline Burré
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Contributions

M.S. and T.C.S. designed the study. M.S. and J.B. performed and analysed the experiments. M.S., J.B. and T.C.S. wrote the manuscript.

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Correspondence to Manu Sharma or Thomas C. Südhof.

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Sharma, M., Burré, J. & Südhof, T. CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. Nat Cell Biol 13, 30–39 (2011). https://doi.org/10.1038/ncb2131

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