Spinocerebellar ataxia type 7 (SCA7), which causes retinal cone-rod degeneration and eventual blindness, can be traced to the expansion of a CAG trinucloetide repeat-from 10 to as many as 250 triplets-in the SCA7 gene. These mutations result in vastly extended polyglutamine (polyQ) tracts in the protein ataxin-7, though how this impacts retinal cells is poorly understood.

A group led by Al LaSpada, University of Washington, Seattle, reports in the September 27 Neuron that transcriptional interference may underlie SCA7. The authors found that ataxin-7 interacts with the cone-rod homeobox protein (CRX), a known retinal transcription factor. The two proteins activate transcription when used as "bait" and "prey" in a yeast two-hybrid assay, and they co-immunoprecipitate in vitro. In mammalian cell culture they co-localize to the nucleus, and a mutated ataxin-7 containing a 92Q tract represses CRX activation of the rhodopsin promoter. Transgenic mice harboring the mutated gene exhibit progressive retinal degeneration, manifested by thinning of the outer nuclear layer, and an increase in nuclear inclusions and apoptotic cells.

Though at least nine polyglutamine neurodegenerative diseases are known, including Huntington's disease, their molecular bases are not well established. However, Harry Orr of the University of Minnesota points out in an accompanying preview that the nucleus is emerging as a common location for interaction of polyQ proteins, suggesting that regulation of transcription may be a common underlying theme.—Tom Fagan

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Primary Papers

  1. . Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron. 2001 Sep 27;31(6):913-27. PubMed.
  2. . Qs in the nucleus. Neuron. 2001 Sep 27;31(6):875-6. PubMed.