DMCA
Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis (2010)
| Venue: | PLoS Genet |
| Citations: | 14 - 3 self |
BibTeX
@ARTICLE{Crespo-barreto10partialloss,
author = {Juan Crespo-barreto and John D. Fryer and Chad A. Shaw and Harry T. Orr and Huda Y. Zoghbi},
title = {Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis},
journal = {PLoS Genet},
year = {2010},
pages = {1001021}
}
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Abstract
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a CAG repeat that encodes a polyglutamine tract in ATAXIN1 (ATXN1). Molecular and genetic data indicate that SCA1 is mainly caused by a gain-of-function mechanism. However, deletion of wild-type ATXN1 enhances SCA1 pathogenesis, whereas increased levels of an evolutionarily conserved paralog of ATXN1, Ataxin 1-Like, ameliorate it. These data suggest that a partial loss of ATXN1 function contributes to SCA1. To address this possibility, we set out to determine if the SCA1 disease model (Atxn1 154Q/+ mice) and the loss of Atxn1 function model (Atxn1 2/2 mice) share molecular changes that could potentially contribute to SCA1 pathogenesis. To identify transcriptional changes that might result from loss of function of ATXN1 in SCA1, we performed gene expression microarray studies on cerebellar RNA from Atxn1 2/2 and Atxn1 154Q/+ cerebella and uncovered shared gene expression changes. We further show that mild overexpression of Ataxin-1-Like rescues several of the molecular and behavioral defects in Atxn1 2/2 mice. These results support a model in which Ataxin 1-Like overexpression represses SCA1 pathogenesis by compensating for a partial loss of function of Atxn1. Altogether, these data provide evidence that partial loss of Atxn1 function contributes to SCA1 pathogenesis and raise the possibility that
Keyphrases
partial loss spinocerebellar ataxia type ataxin-1 function contributes transcriptional dysregulation sca1 pathogenesis atxn1 function contributes gene expression change atxn1 function model transcriptional change wild-type atxn1 enhances sca1 pathogenesis polyglutamine tract gene expression microarray study gain-of-function mechanism cerebellar rna neurodegenerative disease share molecular change mild overexpression sca1 disease model ataxin-1-like rescue genetic data indicate cag repeat behavioral defect
