CSPalpha-deficiency causes massive and rapid photoreceptor degeneration.
Cysteine string protein (CSP) alpha is an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed that deletion of CSPalpha in mice leads to massive lethal neurodegeneration but did not clarify how the neurodegeneration affects specific subpopulations of neurons. Here, we analyzed the effects of the CSPalpha deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSPalpha-deficient photoreceptor terminals undergo dramatic and rapidly progressive neurodegeneration that starts before eye opening and initially does not affect other retinal synapses. These changes are associated with progressive blindness. In contrast, ribbon synapses of auditory hair cells did not exhibit presynaptic impairments in CSPalpha-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSPbeta, thereby accounting for the lack of a hair-cell phenotype in CSPalpha knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSPalpha and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration.
Schmitz
Frank
F
Institut für Anatomie und Zellbiologie, Universität des Saarlandes Homburg/Saar, Homburg, 66421 Saarland, Germany. frank.schmitz@uniklinik-saarland.de
Tabares
Lucia
L
Khimich
Darina
D
Strenzke
Nicola
N
de la Villa-Polo
Pedro
P
Castellano-Muñoz
Manuel
M
Bulankina
Anna
A
Moser
Tobias
T
Fernández-Chacón
Rafael
R
Südhof
Thomas C
TC
D000818:Animals; D001766:Blindness / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D050956:HSP40 Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006199:Hair Cells, Auditory, Inner / Q000166:cytology / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000648:ultrastructure*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000648:ultrastructure*
D002352:Carrier Proteins; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C088460:cysteine string protein