Polyglutamine-Expanded Ataxin-7 Antagonizes CRX Function and Induces Cone-Rod Dystrophy in a Mouse Model of SCA7

• Published in: Neuron (Cambridge, Mass.) Vol. 31; no. 6; pp. 913 - 927
• Main Authors: La Spada, Albert R., Fu, Ying-Hui, Sopher, Bryce L., Libby, Randell T., Wang, Xuejiao, Li, Lili Y., Einum, David D., Huang, Jing, Possin, Daniel E., Smith, Annette C., Martinez, Refugio A., Koszdin, Kari L., Treuting, Piper M., Ware, Carol B., Hurley, James B., Ptáček, Louis J., Chen, Shiming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.09.2001
• Subjects: Age Factors; Animals; Ataxin-7; Cell Line; Cell Nucleus - metabolism; Cell Nucleus - ultrastructure; CRX protein; Disease Models, Animal; Electroretinography; Eye Proteins - chemistry; Eye Proteins - genetics; Eye Proteins - physiology; Gene Expression Profiling; Genes, Synthetic; Homeodomain Proteins - antagonists & inhibitors; Homeodomain Proteins - physiology; Humans; Macromolecular Substances; Mice; Mice, Transgenic; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Peptides - chemistry; Photoreceptor Cells, Vertebrate - metabolism; polyglutamine; Prions - genetics; Promoter Regions, Genetic; Protein Binding; Retinal Degeneration - genetics; Retinal Degeneration - metabolism; Spinocerebellar ataxia; Spinocerebellar ataxia 7; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - metabolism; Synaptic Transmission; Trans-Activators - antagonists & inhibitors; Trans-Activators - physiology; Transcriptional Activation; Transfection; Transgenes; Trinucleotide Repeats; Two-Hybrid System Techniques
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/S0896-6273(01)00422-6

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.