Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice.
Shanshan Huang, Su Yang, Jifeng Guo, Sen Yan, Marta A Gaertig, Shihua Li, Xiao-Jiang Li
Author Information
Shanshan Huang: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
Su Yang: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
Jifeng Guo: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
Sen Yan: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 10010, China.
Marta A Gaertig: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
Shihua Li: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA. Electronic address: sli@emory.edu.
Xiao-Jiang Li: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 10010, China. Electronic address: xjli@genetics.ac.cn.
In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than those of adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knockin mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA-box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP's interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases.
