CSPα-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 CSP alpha 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 CSP alpha deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSP alpha-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 CSP alpha-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSP beta, thereby accounting for the lack of a hair-cell phenotype in CSP alpha knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSP alpha and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration.