Abstract
Cysteine string protein α (CSPα)—an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40 chaperones—is thought to regulate Ca 2+ channels and/or synaptic vesicle exocytosis. We now show that, in young mice, deletion of CSPα does not impair survival and causes no significant changes in presynaptic Ca 2+ currents or synaptic vesicle exocytosis as measured in the Calyx of Held synapse. At 2–4 weeks of age, however, CSPα-deficient mice develop a progressive, fatal sensorimotor disorder. The neuromuscular junctions and Calyx synapses of CSPα-deficient mice exhibit increasing neurodegenerative changes, synaptic transmission becomes severely impaired, and the mutant mice die at ∼2 months of age. Our data suggest that CSPα is not essential for the normal operation of Ca 2+ channels or exocytosis but acts as a presynaptic chaperone that maintains continued synaptic function, raising the possibility that enhanced CSPα function could attenuate neurodegenerative diseases.
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