DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5
DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5
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DOI：
10.15252/emmm.201708547
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发表时间：
2019-05-01
影响因子：
11.1
通讯作者：
Katsuno, Masahisa
中科院分区：
文献类型：
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作者：
Kondo, Naohide;Tohnai, Genki;Katsuno, Masahisa
脊髓和球部肌萎缩症(SBMA)是一种由雄激素受体(AR)基因CAG重复扩增引起的多谷氨酰胺介导的神经肌肉疾病。虽然转录调控失调在SBMA的发病机制中起着关键作用，但其潜在的分子发病机制仍不清楚。DNA甲基化是一种基本的表观遗传修饰，它可以沉默具有丰富CpG启动子的各种基因的转录。在这里，我们发现DNA甲基转移酶1(DNMT1)在SBMA小鼠模型和SBMA患者的脊髓运动神经元中高表达。Dnmt1基因缺失和DNA甲基化抑制剂RG108治疗均可改善SBMA模型细胞的活力。此外，连续脑室注射RG108可减轻SBMA小鼠的表型。DNA甲基化阵列分析证实，Hes5的毛发和增强子在启动子区域有一个高甲基化的CpG岛，并且Hes5在SBMA中的表达被强烈沉默。此外，Hes5的过表达可能通过诱导Smad2的磷酸化来拯救SBMA细胞。我们的发现表明，DNA超甲基化是SBMA神经变性的基础。
Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG-rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper-methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over-expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper-methylation underlies the neurodegeneration in SBMA.