La Spada et al. may provide a clue to solving this mystery. In the 27 September issue of Neuron, they report that transcriptional interference of cell-specific genes may be responsible for the specific pattern of degeneration seen in one type of polyglutamine disease, spinocerebellar ataxia type 7 (SCA7). SCA7 is unique among the spinocerebellar ataxias because it also causes retinal degeneration. La Spada et al. find that the protein encoded by the SCA7 gene, ataxin-7, interacts with CRX, a homeobox protein in rods and cones. CRX encodes a nuclear transcription factor containing a polyglutamine-rich region, and controls the expression of several photoreceptor-specific genes, including rhodopsin and the color opsins. Moreover, the polyglutamine-expanded ataxin-7 suppresses CRX transactivation. In SCA7 mutant mice, where ataxin-7 forms nuclear aggregates (magenta, see arrows in picture) in all three nuclear layers of the retina (photoreceptor nuclei in the outer nuclear layer and neuronal nuclei in the inner nuclear layer are blue in picture, whereas the nuclei in the ganglion cell layer are colored red), the authors find that the ability of CRX to bind to its consenus sequence is diminished, and that the expression of CRX-regulated genes is reduced in the retinas of these presymptomatic mutant mice.
It would seem, from these results, that ataxin-7–mediated transcription interference of photoreceptor genes might account for the cone and rod dystrophy seen in SCA7. If generalized to other polyglutamine diseases, this suggests that transcriptional interference of a cell-type–specific transcription factor could be a common mechanism that would also produce cell-specific pathology.
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