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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Age Factors
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Animals
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Ataxin-7
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Cell Line
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Cell Nucleus / metabolism*
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Cell Nucleus / ultrastructure
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Disease Models, Animal
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Electroretinography
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Eye Proteins / chemistry
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Eye Proteins / genetics
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Eye Proteins / physiology
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Gene Expression Profiling
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Genes, Synthetic
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Homeodomain Proteins / antagonists & inhibitors*
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Homeodomain Proteins / physiology
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Humans
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Macromolecular Substances
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Mice
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Mice, Transgenic
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Peptides / chemistry*
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Photoreceptor Cells, Vertebrate / metabolism
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Prions / genetics
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Promoter Regions, Genetic
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Protein Binding
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Retinal Degeneration / genetics
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Retinal Degeneration / metabolism
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Spinocerebellar Ataxias / genetics
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Spinocerebellar Ataxias / metabolism
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Synaptic Transmission
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / physiology
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Transcriptional Activation
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Transfection
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Transgenes
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Trinucleotide Repeats*
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Two-Hybrid System Techniques
Substances
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ATXN7 protein, human
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Ataxin-7
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Atxn7 protein, mouse
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Eye Proteins
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Homeodomain Proteins
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Macromolecular Substances
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Prions
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Trans-Activators
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cone rod homeobox protein
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polyglutamine