title: Identification of CSPα clients reveals a role in dynamin 1 regulation.
abstract: 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.
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Neurology, Yale University, New Haven, CT 06536, USA.
authors.forename: Yong-Quan
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Michael X
authors.initials: MX
authors.lastname: Henderson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Colangelo
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.forename: Can
authors.initials: C
authors.lastname: Bruce
authors.forename: Terence
authors.initials: T
authors.lastname: Wu
authors.forename: Sreeganga S
authors.initials: SS
authors.lastname: Chandra
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D034284:Dynamin I / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D016555:Matched-Pair Analysis; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000145:classification / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D040901:Proteomics; D012016:Reference Values; D013569:Synapses / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050825:Synaptosomal-Associated Protein 25; C088460:cysteine string protein; D034284:Dynamin I