title: Mutant huntingtin downregulates myelin regulatory factor-mediated myelin gene expression and affects mature oligodendrocytes.
abstract: Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington's disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remains unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knockin mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target.
authors: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors: Brenda
authors: B
authors: Huang
authors: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
authors: WenJie
authors: W
authors: Wei
authors: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors: Guohao
authors: G
authors: Wang
authors: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors: Marta A
authors: MA
authors: Gaertig
authors: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
authors: Yue
authors: Y
authors: Feng
authors: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
authors: Wei
authors: W
authors: Wang
authors: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China. Electronic address: xli2@emory.edu.
authors: Xiao-Jiang
authors: XJ
authors: Li
authors: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China. Electronic address: sli@emory.edu.
authors: Shihua
authors: S
authors: Li
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C571125:myelin gene regulatory factor, mouse