NR AGYI
AU La Spada,A.R.; Fu,Y.H.; Sopher,B.L.; Libby,R.T.; Wang,X.; Li,L.Y.; Einum,D.D.; Huang,J.; Possin,D.E.; Smith,A.C.; Martinez,R.A.; Koszdin,K.L.; Treuting,P.M.; Ware,C.B.; Hurley,J.B.; Ptacek,L.J.; Chen,S.
TI Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7
QU Neuron 2001 Sep 27; 31(6): 913-27
KI Neuron. 2001 Sep 27;31(6):875-6. PMID: 11580886
ER Neuron 2001 Dec 6;32(5):957-8
PT journal article
AB 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.
MH Age Factors; Animal; 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; Human; Macromolecular Systems; Mice; Mice, Transgenic; Nerve Tissue Proteins/chemistry/deficiency/genetics/*physiology; Nuclear Proteins/chemistry/genetics/*physiology; Peptides/*chemistry; Photoreceptors, Vertebrate/metabolism; Prions/genetics; Promoter Regions (Genetics); Protein Binding; Retinal Degeneration/genetics/metabolism; Spinocerebellar Ataxias/genetics/metabolism; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Synaptic Transmission; Trans-Activation (Genetics); Trans-Activators/*antagonists & inhibitors/physiology; Transfection; Transgenes; *Trinucleotide Repeats; Two-Hybrid System Techniques
AD Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA 98195, USA. laspada@u.washington.edu
SP englisch
PO USA