Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis.

Juan Crespo-Barreto, John D. Fryer, Chad A. Shaw, Harry T. Orr, Huda Y. Zoghbi

Research output: Contribution to journalArticle

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-/- 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-/- 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-/- 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 loss-of-function mechanisms contribute to other dominantly inherited neurodegenerative diseases.

Original languageEnglish (US)
JournalPLoS Genetics
Volume6
Issue number7
StatePublished - Jul 2010
Externally publishedYes

Fingerprint

Spinocerebellar Ataxias
pathogenesis
neurodegenerative diseases
gene expression
disease models
mice
cerebellum
Neurodegenerative Diseases
animal models
RNA
defect
Gene Expression
Ataxin-1
loss
Cerebellum
Molecular Biology

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. / Crespo-Barreto, Juan; Fryer, John D.; Shaw, Chad A.; Orr, Harry T.; Zoghbi, Huda Y.

In: PLoS Genetics, Vol. 6, No. 7, 07.2010.

Research output: Contribution to journalArticle

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