2019 Fiscal Year Final Research Report

Elucidation of defective neural communication in motor neuron diseases

Research Project

PDF

Project/Area Number	17H04195
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Neurology
Research Institution	Nagoya University
Principal Investigator	Katsuno Masahisa 名古屋大学, 医学系研究科, 教授 (50402566)
Co-Investigator(Kenkyū-buntansha)	橋詰淳名古屋大学, 医学部附属病院, 病院助教 (00637689) 井口洋平名古屋大学, 医学部附属病院, 助教 (80790659) 佐橋健太郎名古屋大学, 医学部附属病院, 病院助教 (90710103)
Project Period (FY)	2017-04-01 – 2020-03-31
Keywords	運動ニューロン疾患 / エクソサイトーシス / インスリン / DNAメチル化 / Src / TDP-43 / アンドロゲン受容体 / カルシウムチャンネル
Outline of Final Research Achievements	Nuclear depletion of TDP-43 is the histopathological hallmark of amyotrophic lateral sclerosis. In this research, we showed that loss of TDP-43 inhibited exocytosis by down-regulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. In this research, we showed that DNA methyltransferase 1 is highly expressed in the motor neurons of an SBMA mouse model, and in patients with SBMA. Treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells and s the motor function of SBMA mice. We also found that the level of phosphorylated Src was markedly increased in the spinal cords and skeletal muscles of SBMA mice prior to the onset, by utilizing a phosphoprotein assay. Intraperitoneal administration of a Src kinase inhibitor improved the behavioral and histopathological phenotypes of SBMA mice.
Free Research Field	神経内科学
Academic Significance and Societal Importance of the Research Achievements	本研究は、ニューロンが細胞外分泌などを介して行っている他の細胞との情報・分子伝達の異常が運動ニューロン疾患における神経・筋システム変性の基盤であるとの仮説に基づき、従来にはない画期的な視点で運動ニューロン疾患の病態の本質を明らかにした。この成果は運動ニューロン疾患の進行メカニズムの解明と、それに基づく予後予測や治療法の開発に直結するだけでなく、認知症を含む他の多くの神経変性疾患や筋疾患などの病態メカニズム研究に応用が可能である。