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Sci Rep. 2016 Aug 12;6:31022. doi: 10.1038/srep31022.

Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity.

Author information

1
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
7
Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, MO 63110, USA.

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.

PMID:
27516062
PMCID:
PMC4981892
DOI:
10.1038/srep31022
[Indexed for MEDLINE]
Free PMC Article

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