DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5

• DOI: 10.15252/emmm.201708547
• Publication Date: 2019-04-02T10:25:15Z
• Authors: Naohide Kondo; Genki Tohnai; Kentaro Sahashi; Madoka Iida; Mayumi Kataoka; Hideaki Nakatsuji; Yutaka Tsutsumi; Atsushi Hashizume; Hiroaki Adachi; Haruki Koike; Keiko Shinjo; Yutaka Kondo; Gen Sobue; Masahisa Katsuno
• Keywords: DNA (Cytosine-5-)-Methyltransferase 1; 0301 basic medicine; Medicine (General); Cell Survival; Phthalimides; Smad2 Protein; QH426-470; Motor Activity; Models, Biological; Muscular Atrophy, Spinal; 03 medical and health sciences; R5-920; Genetics; Basic Helix-Loop-Helix Transcription Factors; Animals; Humans; Promoter Regions, Genetic; Research Articles; Aged; Motor Neurons; DNA methylation; epigenetics; spinal and bulbar muscular atrophy; RG108; DNA Methylation; Middle Aged; Mice, Inbred C57BL; Repressor Proteins; Receptors, Androgen; Nerve Degeneration; Hes5; Peptides

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.