Exercise and Genetic Rescue of SCA1 via the Transcriptional Repressor Capicua

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 surviv...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2011-11, Vol.334 (6056), p.690-693
Main Authors: Fryer, John D., Yu, Peng, Kang, Hyojin, Mandel-Brehm, Caleigh, Carter, Angela N., Crespo-Barreto, Juan, Gao, Yan, Flora, Adriano, Shaw, Chad, Orr, Harry T., Zoghbi, Huda Y.
Format: Article
Language:English
Subjects:
Animals
Ataxia
Ataxin-1
Ataxins
Biological and medical sciences
Brain stem
Cerebellum
Cerebellum - metabolism
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Disease Models, Animal
Exercise
Exercise Therapy
Fatal
Fundamental and applied biological sciences. Psychology
Gain
Gene Knock-In Techniques
Genetics
Genotypes
Growth factors
Life span
Mathematical models
Medical genetics
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Molecular and cellular biology
Molecular genetics
Nerve Tissue Proteins - genetics
Nervous system diseases
Neurodegenerative diseases
Neurological disorders
Neurology
Nuclear Proteins - genetics
Phenotypes
Purkinje cells
Repressor Proteins - genetics
Repressor Proteins - physiology
Rodents
Spinocerebellar Ataxias - genetics
Spinocerebellar Ataxias - therapy
Survival
Transcription. Transcription factor. Splicing. Rna processing
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Summary: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 Capicúa 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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1212673