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 affect...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (8), p.2926-2931
Main Authors: Schmitz, Frank, Tabares, Lucia, Khimich, Darina, Strenzke, Nicola, de la Villa-Polo, Pedro, Castellano-Muñoz, Manuel, Bulankina, Anna, Moser, Tobias, Fernández-Chacón, Rafael, Südhof, Thomas C
Format: Article
Language:English
Subjects:
Animals
Blindness - genetics
Blindness - metabolism
Blindness - pathology
Carrier Proteins - genetics
Carrier Proteins - physiology
Cells
Hair Cells, Auditory, Inner - cytology
Hair Cells, Auditory, Inner - physiology
HSP40 Heat-Shock Proteins - deficiency
HSP40 Heat-Shock Proteins - genetics
HSP40 Heat-Shock Proteins - physiology
Membrane Proteins - deficiency
Membrane Proteins - genetics
Membrane Proteins - physiology
Mice
Mice, Knockout
Nerve Tissue Proteins - deficiency
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - physiology
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - metabolism
Neurodegenerative Diseases - pathology
Neurons
Neurosciences
Photoreceptor Cells, Vertebrate - metabolism
Photoreceptor Cells, Vertebrate - ultrastructure
Proteins
Retina - metabolism
Retina - pathology
Rodents
Synapses - ultrastructure
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Summary: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.
ISSN:0027-8424
1091-6490