title: Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity.
abstract: Although epigenetic abnormalities have been described in Huntington's disease (HD), the causal epigenetic mechanisms driving neurodegeneration in HD cortex and striatum remain undefined. Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression. Inhibition of DNMTs in HD model primary cortical or striatal neurons restored the expression of several key genes, including Bdnf, an important neurotrophic factor implicated in HD. Accordingly, the Bdnf promoter exhibited aberrant cytosine methylation in mutant Htt-expressing cortical neurons. In vivo, pharmacological inhibition of DNMTs in HD mouse brains restored the mRNA levels of key striatal genes known to be downregulated in HD. Thus, disturbances in DNA methylation play a critical role in mutant Htt-induced neuronal dysfunction and death, raising the possibility that epigenetic strategies targeting abnormal DNA methylation may have therapeutic utility in HD.
authors: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Yanchun
authors: Y
authors: Pan
authors: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Takuji
authors: T
authors: Daito
authors: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Yo
authors: Y
authors: Sasaki
authors: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Yong Hee
authors: YH
authors: Chung
authors: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Xiaoyun
authors: X
authors: Xing
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Santhi
authors: S
authors: Pondugula
authors: Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: S Joshua
authors: SJ
authors: Swamidass
authors: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Ting
authors: T
authors: Wang
authors: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Albert H
authors: AH
authors: Kim
authors: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Hiroko
authors: H
authors: Yano
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000037:antagonists & inhibitors*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein / Q000633:toxicity*; D006816:Huntington Disease / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D050505:Mutant Proteins / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000502:physiology
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619381:Dnmt1 protein, mouse