Neuron
Volume 74, Issue 1, 12 April 2012, Pages 136-150
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Article
Identification of CSPα Clients Reveals a Role in Dynamin 1 Regulation

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Summary

Cysteine string protein α (CSPα), a presynaptic cochaperone for Hsc70, is required for synapse maintenance. Deletion of CSPα leads to neuronal dysfunction, synapse loss, and neurodegeneration. We utilized unbiased, systematic proteomics to identify putative CSPα protein clients. We found 22 such proteins whose levels are selectively decreased in CSPα knockout synapses. Of these putative CSPα protein clients, two directly bind to the CSPα chaperone complex and are bona fide clients. They are the t-SNARE SNAP-25 and the GTPase dynamin 1, which are necessary for synaptic vesicle fusion and fission, respectively. Using hippocampal cultures, we show that CSPα regulates the stability of client proteins and synaptic vesicle number. Our analysis of CSPα-dynamin 1 interactions reveals unexpectedly that CSPα regulates the polymerization of dynamin 1. CSPα, therefore, participates in synaptic vesicle endocytosis and may facilitate exo- and endocytic coupling. These findings advance the understanding of how synapses are functionally and structurally maintained.

Highlights

► CSPα is required for synapse maintenance ► Quantitative proteomics identified 22 putative CSPα clients ► CSPα chaperones SNAP-25 and dynamin 1, coupling exocytosis and endocytosis ► CSPα promotes dynamin 1 oligomerization

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These authors contributed equally to this work