title: Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Sen
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Gaertig
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA. Electronic address: sli@emory.edu.
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000818:Animals; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035181:TATA-Box Binding Protein / Q000235:genetics* / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D023081:CCAAT-Binding Factor; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C492060:Nfya protein, mouse; D010455:Peptides; D035181:TATA-Box Binding Protein; C097188:polyglutamine