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

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.

Pubmed ID: 11580893


  • La Spada AR
  • Fu YH
  • Sopher BL
  • Libby RT
  • Wang X
  • Li LY
  • Einum DD
  • Huang J
  • Possin DE
  • Smith AC
  • Martinez RA
  • Koszdin KL
  • Treuting PM
  • Ware CB
  • Hurley JB
  • Pt├ícek LJ
  • Chen S



Publication Data

September 27, 2001

Associated Grants

  • Agency: NEI NIH HHS, Id: EY01730
  • Agency: NEI NIH HHS, Id: EY02687
  • Agency: NEI NIH HHS, Id: EY06641
  • Agency: NEI NIH HHS, Id: EY12543
  • Agency: NEI NIH HHS, Id: R01 EY012543

Mesh Terms

  • Age Factors
  • Animals
  • Cell Line
  • Cell Nucleus
  • Disease Models, Animal
  • Electroretinography
  • Eye Proteins
  • Gene Expression Profiling
  • Genes, Synthetic
  • Homeodomain Proteins
  • Humans
  • Macromolecular Substances
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Photoreceptor Cells, Vertebrate
  • Prions
  • Promoter Regions, Genetic
  • Protein Binding
  • Retinal Degeneration
  • Spinocerebellar Ataxias
  • Synaptic Transmission
  • Trans-Activators
  • Transcriptional Activation
  • Transfection
  • Transgenes
  • Trinucleotide Repeats
  • Two-Hybrid System Techniques