Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7.
Neuron
; 31(6): 913-27, 2001 Sep 27.
Article
em En
| MEDLINE
| ID: mdl-11580893
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.
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Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Proteínas Nucleares
/
Transativadores
/
Núcleo Celular
/
Proteínas de Homeodomínio
/
Repetições de Trinucleotídeos
/
Proteínas do Tecido Nervoso
Idioma:
En
Ano de publicação:
2001
Tipo de documento:
Article