title: Effects on murine behavior and lifespan of selectively decreasing expression of mutant huntingtin allele by supt4h knockdown.
abstract: Production of protein containing lengthy stretches of polyglutamine encoded by multiple repeats of the trinucleotide CAG is a hallmark of Huntington's disease (HD) and of a variety of other inherited degenerative neurological and neuromuscular disorders. Earlier work has shown that interference with production of the transcription elongation protein SUPT4H results in decreased cellular capacity to transcribe mutant huntingtin gene (Htt) alleles containing long CAG expansions, but has little effect on expression of genes containing short CAG stretches. zQ175 and R6/2 are genetically engineered mouse strains whose genomes contain human HTT alleles that include greatly expanded CAG repeats and which are used as animal models for HD. Here we show that reduction of SUPT4H expression in brains of zQ175 mice by intracerebroventricular bolus injection of antisense 2'-O-methoxyethyl oligonucleotides (ASOs) directed against Supt4h, or in R6/2 mice by deletion of one copy of the Supt4h gene, results in a decrease in mRNA and protein encoded specifically by mutant Htt alleles. We further show that reduction of SUPT4H in mouse brains is associated with decreased HTT protein aggregation, and in R6/2 mice, also with prolonged lifespan and delay of the motor impairment that normally develops in these animals. Our findings support the view that targeting of SUPT4H function may be useful as a therapeutic countermeasure against HD.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Cheng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: I-Hui
authors.initials: IH
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Chia-Rung
authors.initials: CR
authors.lastname: Liu
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Sih-Huei
authors.initials: SH
authors.lastname: Li
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Chun
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Deng
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Pathology and Cell Biology & Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, United States of America.
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Yan
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Stanley N
authors.initials: SN
authors.lastname: Cohen
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China; Brain Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Cheng
mesh_terms: D000483:Alleles; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D066263:Protein Aggregation, Pathological / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C484413:Supt4h protein, mouse