Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity.
Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity.
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DOI：
10.1038/srep31022
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发表时间：
2016-08-12
影响因子：
4.6
通讯作者：
Yano H
中科院分区：
文献类型：
--
作者：
Pan Y;Daito T;Sasaki Y;Chung YH;Xing X;Pondugula S;Swamidass SJ;Wang T;Kim AH;Yano H
尽管在亨廷顿氏病（HD）中已经描述了表观遗传异常，但驱动HD皮质和纹状体神经变性的因果表观遗传机制仍不明确。使用表观遗传途径靶向药物筛选，我们报告说，抑制剂的DNA甲基转移酶（DNMT），地西他滨和FdCyd，块突变亨廷顿蛋白（Htt）诱导的毒性在初级皮质和纹状体神经元。此外，DNMT3A或DNMT1的敲低保护神经元免受突变体Htt诱导的毒性，共同证明了突变体Htt触发的神经元死亡中对DNMT的需求，并表明基于DNA甲基化介导的转录抑制的神经退行性机制。在HD模型中抑制DNMT可以恢复几个关键基因的表达，包括与HD有关的重要神经营养因子BDNF。因此，Bdnf启动子表现出异常的胞嘧啶甲基化的突变体Htt表达皮层神经元。在体内，药物抑制HD小鼠脑中的DNMT恢复了已知在HD中下调的关键纹状体基因的mRNA水平。因此，DNA甲基化的干扰在突变型Htt诱导的神经元功能障碍和死亡中起关键作用，提高了针对异常DNA甲基化的表观遗传策略在HD中可能具有治疗效用的可能性。
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.