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Description:
Synapse maintenance is important for the preservation of neuronal circuitry and normal behavior. Cysteine string protein α (CSPα) is one of the few presynaptic proteins known to participate in synapse maintenance. Deletion of CSPα, a co-chaperone for Hsc70, leads to impairment in local protein homeostasis resulting in synaptic dysfunction as well as synapse and neuronal loss. Here, we sought to identify the repertoire of CSPα clients with the aim of understanding the CSPα's role in synapse function and stability. Based on the rationale that CSPα clients are misfolded in CSPα knockout (KO) and thereby decreased in at synapses, we utilized unbiased proteomic methods to compare the synaptic proteome of littermate wildtype and CSPα KO mice. Using this strategy, we identified and validated that the levels of 19 synaptic proteins were selectively decreased in CSPα KO synapses. By performing a secondary screen with these proteins for direct binding to CSPα, we identified 2 key CSPα clients. They are SNAP-25, a previously identified client of CSPα, and dynamin 1, the GTPase that regulates synaptic vesicle fission. Using hippocampal cultures derived from CSPα KO mice, we show that CSPα regulates the stability of both SNAP-25 and dynamin 1. We then investigated CSPα's interaction with dynamin 1. Our analysis revealed that CSPα regulates the polymerization of dynamin1 and thereby synaptic vesicle endocytosis. Our data provide mechanistic insight into the dual functions of CSPα in both the exo- and endocytic arms of the synaptic vesicle cycle and advance our understanding of how synapses are maintained functionally and structurally. Finally, we show the involvement of CSPα-dependent synapse maintenance in disease states as Alzheimer's disease brains have a selective reduction in levels of CSPα.
Publications:
Zhang YQ, Henderson MX, Colangelo CM, Ginsberg SD, Bruce C, Wu T, Chandra SS. (2012) Neuron. 2012 Apr 12;74(1):136-50. Identification of CSPĪ± clients reveals a role in dynamin 1 regulation. PubMed
Acknowledgement: This work was supported by the YCCI Scholar Award (CTSA Grant UL1 RR024139; to S.S.C.), R01NS064963 (to S.S.C.), an Anonymous Foundation (to S.S.C.), W.M. Keck Foundation grant (to S.S.C.), NIDA Neuroproteomic Pilot Grant (5 P30 DA018343-07; to S.S.C.), Anderson Fellowship (to Y-Q.Z.), NSF Graduate Research Fellowship (to M.X.H.), and AG14449 (to S.D.G.).
45 results available, displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5 [Next/Last]
Analysis Type Sample Name Search Engine Database Date User/PI
DIGE DIGE_GEL896 info MASCOT IPI_mouse 2008-12-15 09:12:08.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL896 info MASCOT NCBInr 2007-12-19 15:38:30.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL896 info MASCOT IPI_mouse Gly-Gly 2008-12-15 09:12:49.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL907 info MASCOT IPI_mouse 2008-12-15 09:15:49.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL907 info MASCOT IPI_mouse Gly-Gly 2008-12-15 09:16:19.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL907 info MASCOT NCBInr 2008-01-03 11:15:50.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL915 info MASCOT NCBInr 2008-02-07 16:15:12.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL926 info MASCOT IPI_mouse_20080907_GlyGly 2008-12-15 09:19:26.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL926 info MASCOT IPI_mouse_20080907 2008-12-15 09:18:57.0 Sreeganga Chandra/Sreeganga Chandra
DIGE DIGE_GEL926 info MASCOT IPI_mouse 2008-03-04 16:59:12.0 Sreeganga Chandra/Sreeganga Chandra
DownLoad Peptide Summary pep_score > pep_homology
DownLoad Peptide Summary (all peptides with protein ids)


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Updated 02 Oct 2014 14:05