Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua

John D. Fryer, Peng Yu, Hyojin Kang, Caleigh Mandel-Brehm, Angela N. Carter, Juan Crespo-Barreto, Yan Gao, Adriano Flora, Chad Shaw, Harry T. Orr, Huda Y. Zoghbi

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93 Scopus citations

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by expansion of a translated CAG repeat in Ataxin-1 (ATXN1). To determine the long-term effects of exercise, we implemented a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival accompanied by up-regulation of epidermal growth factor and consequential down-regulation of Capicua, which is an ATXN1 interactor. Offspring of Capicua mutant mice bred to SCA1 mice showed significant improvement of all disease phenotypes. Although polyglutamine-expanded Atxn1 caused some loss of Capicua function, further reduction of Capicua levels - either genetically or by exercise - mitigated the disease phenotypes by dampening the toxic gain of function. Thus, exercise might have long-term beneficial effects in other ataxias and neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)690-693
Number of pages4
JournalScience
Volume334
Issue number6056
DOIs
StatePublished - Nov 4 2011

ASJC Scopus subject areas

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    Fryer, J. D., Yu, P., Kang, H., Mandel-Brehm, C., Carter, A. N., Crespo-Barreto, J., Gao, Y., Flora, A., Shaw, C., Orr, H. T., & Zoghbi, H. Y. (2011). Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science, 334(6056), 690-693. https://doi.org/10.1126/science.1212673