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.
Authors	A R La Spada, Y H Fu, B L Sopher, R T Libby, X Wang, L Y Li, D D Einum, J Huang, D E Possin, A C Smith, R A Martinez, K L Koszdin, P M Treuting, C B Ware, J B Hurley, L J Ptácek, S Chen
Journal	Neuron (Neuron) Vol. 31 Issue 6 Pg. 913-27 (Sep 27 2001) ISSN: 0896-6273 [Print] United States
PMID	11580893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	ATXN7 protein, human Ataxin-7 Atxn7 protein, mouse Eye Proteins Homeodomain Proteins Macromolecular Substances Nerve Tissue Proteins Nuclear Proteins Peptides Prions Trans-Activators cone rod homeobox protein polyglutamine
Topics	Age Factors Animals Ataxin-7 Cell Line Cell Nucleus (metabolism, ultrastructure) Disease Models, Animal Electroretinography Eye Proteins (chemistry, genetics, physiology) Gene Expression Profiling Genes, Synthetic Homeodomain Proteins (antagonists & inhibitors, physiology) Humans Macromolecular Substances Mice Mice, Transgenic Nerve Tissue Proteins (chemistry, deficiency, genetics, physiology) Nuclear Proteins (chemistry, genetics, physiology) Peptides (chemistry) Photoreceptor Cells, Vertebrate (metabolism) Prions (genetics) Promoter Regions, Genetic Protein Binding Retinal Degeneration (genetics, metabolism) Spinocerebellar Ataxias (genetics, metabolism) Synaptic Transmission Trans-Activators (antagonists & inhibitors, physiology) Transcriptional Activation Transfection Transgenes Trinucleotide Repeats Two-Hybrid System Techniques

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