The synaptic vesicle protein CSP alpha prevents presynaptic degeneration.
Cysteine string protein alpha (CSPalpha)--an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40 chaperones--is thought to regulate Ca2+ channels and/or synaptic vesicle exocytosis. We now show that, in young mice, deletion of CSPalpha does not impair survival and causes no significant changes in presynaptic Ca2+ currents or synaptic vesicle exocytosis as measured in the Calyx of Held synapse. At 2-4 weeks of age, however, CSPalpha-deficient mice develop a progressive, fatal sensorimotor disorder. The neuromuscular junctions and Calyx synapses of CSPalpha-deficient mice exhibit increasing neurodegenerative changes, synaptic transmission becomes severely impaired, and the mutant mice die at approximately 2 months of age. Our data suggest that CSPalpha is not essential for the normal operation of Ca2+ channels or exocytosis but acts as a presynaptic chaperone that maintains continued synaptic function, raising the possibility that enhanced CSPalpha function could attenuate neurodegenerative diseases.
Fernández-Chacón
Rafael
R
Center for Basic Neuroscience, Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75390, USA.
Wölfel
Markus
M
Nishimune
Hiroshi
H
Tabares
Lucia
L
Schmitz
Frank
F
Castellano-Muñoz
Manuel
M
Rosenmund
Christian
C
Montesinos
Maria L
ML
Sanes
Joshua R
JR
Schneggenburger
Ralf
R
Südhof
Thomas C
TC
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein