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Science 334 (6056): 690-693

Copyright © 2011 by the American Association for the Advancement of Science

Exercise and Genetic Rescue of SCA1 via the Transcriptional Repressor Capicua

John D. Fryer,1,* Peng Yu,1 Hyojin Kang,1 Caleigh Mandel-Brehm,1 Angela N. Carter,2 Juan Crespo-Barreto,1,{dagger} Yan Gao,1 Adriano Flora,1 Chad Shaw,1,3 Harry T. Orr,4 Huda Y. Zoghbi1,2,5,6,7,{ddagger}

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.

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
3 Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
4 Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
5 Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
6 Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA.
7 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

* Present address: Department of Neuroscience, Mayo Clinic, FL 32224, USA.

{dagger} Present address: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

{ddagger} To whom correspondence should be addressed. E-mail: hzoghbi{at}bcm.edu


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