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.
authors.affiliation: Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA 98195, USA. laspada@u.washington.edu
authors.forename: A R
authors.initials: AR
authors.lastname: La Spada
authors.forename: Y H
authors.initials: YH
authors.lastname: Fu
authors.forename: B L
authors.initials: BL
authors.lastname: Sopher
authors.forename: R T
authors.initials: RT
authors.lastname: Libby
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: L Y
authors.initials: LY
authors.lastname: Li
authors.forename: D D
authors.initials: DD
authors.lastname: Einum
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: D E
authors.initials: DE
authors.lastname: Possin
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: R A
authors.initials: RA
authors.lastname: Martinez
authors.forename: K L
authors.initials: KL
authors.lastname: Koszdin
authors.forename: P M
authors.initials: PM
authors.lastname: Treuting
authors.forename: C B
authors.initials: CB
authors.lastname: Ware
authors.forename: J B
authors.initials: JB
authors.lastname: Hurley
authors.forename: L J
authors.initials: LJ
authors.lastname: Ptácek
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000818:Animals; D000067719:Ataxin-7; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D005813:Genes, Synthetic; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010455:Peptides / Q000737:chemistry*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D011328:Prions / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D019076:Transgenes; D018911:Trinucleotide Repeats; D020798:Two-Hybrid System Techniques
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D005136:Eye Proteins; D018398:Homeodomain Proteins; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011328:Prions; D015534:Trans-Activators; C109288:cone rod homeobox protein; C097188:polyglutamine