Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7

Albert R. La Spada, Ying Hui Fu, Bryce L. Sopher, Randell T. Libby, Xuejiao Wang, Lili Y. Li, David D. Einum, Jing Huang, Daniel E. Possin, Annette C. Smith, Refugio A. Martinez, Kari L. Koszdin, Piper M. Treuting, Carol B. Ware, James B. Hurley, Louis J. Ptáček, Shiming Chen

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221 Scopus citations


Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder caused by a CAG repeat expansion. To determine the mechanism of neurotoxicity, we produced transgenic mice and observed a cone-rod dystrophy. Nuclear inclusions were present, suggesting that the disease pathway involves the nucleus. When yeast two-hybrid assays indicated that cone-rod homeobox protein (CRX) interacts with ataxin-7, we performed further studies to assess this interaction. We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation. In SCA7 transgenic mice, electrophoretic mobility shift assays indicated reduced CRX binding activity, while RT-PCR analysis detected reductions in CRX-regulated genes. Our results suggest that CRX transcription interference accounts for the retinal degeneration in SCA7 and thus may provide an explanation for how cell-type specificity is achieved in this polyglutamine repeat disease.

Original languageEnglish
Pages (from-to)913-927
Number of pages15
Issue number6
StatePublished - Sep 27 2001


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