@article{08b15f2686a0481dadc8d77fdb13eb65,
title = "Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7",
abstract = "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.",
author = "\{La Spada\}, \{Albert R.\} and Fu, \{Ying Hui\} and Sopher, \{Bryce L.\} and Libby, \{Randell T.\} and Xuejiao Wang and Li, \{Lili Y.\} and Einum, \{David D.\} and Jing Huang and Possin, \{Daniel E.\} and Smith, \{Annette C.\} and Martinez, \{Refugio A.\} and Koszdin, \{Kari L.\} and Treuting, \{Piper M.\} and Ware, \{Carol B.\} and Hurley, \{James B.\} and Pt{\'a}{\v c}ek, \{Louis J.\} and Shiming Chen",
note = "Funding Information: We thank B. McMahan, M. Durning, and S. Xu for technical assistance; G. Nicholson, J. Christodoulou, and T. Bird for patient samples; D. Borchelt for the MoPrP vector; J.P. Taylor for the AR expression vector; A. Swaroop for the pcDNA3.1-NRL vector; J. Nathans for the cone opsin antibodies and cDNA plasmids; T. Furukawa for photoreceptor gene probes; S. Elledge for positive control bait and prey plasmids; R. Bremner for the Gal4-VP16 vector; and R. Palmiter for critical reading of the manuscript. We are especially grateful to J. Saari, R. Morrison, A. Milam, Y. Kinoshita, and G. Garden for their help. This work was supported by National Institutes of Health grants EY01730 (UWMC), EY06641 (J.B.H.), EY12543 (S.C.), EY02687 (WUDOVS); a Career Development Award from RPB (S.C.); a Postdoctoral Fellowship from Fight for Sight (X.W.); a generous gift from a Utah SCA7 family (Y.-H.F.); and by research funds provided by the University of Washington, Department of Laboratory Medicine (A.R.L.).",
year = "2001",
month = sep,
day = "27",
doi = "10.1016/S0896-6273(01)00422-6",
language = "English",
volume = "31",
pages = "913--927",
journal = "Neuron",
issn = "0896-6273",
number = "6",
}