CSPα-deficiency causes massive and rapid photoreceptor degeneration

Cysteine string protein (CSP) α is an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed that deletion of CSPα 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 CSPα deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSPα-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 CSPα-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSPβ, thereby accounting for the lack of a hair-cell phenotype in CSPα knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSPα and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration.