Epigenetic mechanism on the pathogenesis of motor neuron disease

2015 Fiscal Year Final Research Report

• Project/Area Number: 26860665
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: Kondo Naohide 名古屋大学, 医学部附属病院, 医員 (20725527)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 球脊髄性筋萎縮症 / エピジェネティクス / DNAメチル化 / DNAメチル化酵素 / DNAメチル化阻害剤 / 神経変性疾患

Outline of Final Research Achievements

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neuromuscular disease caused by the expansion of a CAG repeat within the first exon of androgen receptor (AR) gene. DNA methylation is the fundamental silencing machinery for several genes with a CpG-rich promoter. The hypothesis of this study is an abnormal DNA hypermethylation in the CpG island of several gene promoters contributes to the transcriptional dysfunction of SBMA. Immunohistochemistry analysis revealed that DNA methyltransferase 1(Dnmt1) expression level of spinal motor neuron in SBMA model mouse was up-regulated compared with that of wild type mouse. RG108, a DNA methyltransferase inhibitor, improved the cell viability of the SBMA model cells. Intraventricular injection of RG108 also mitigated the mortality and motor dysfunction of the model mice. These results indicate that pharmacological blockade of DNA methylation is a therapeutic candidate for SBMA.

Free Research Field

神経内科学