Investigation of ALS/FTLD pathogenesis based on translational deterioration due to ribosome dysfunction in axons

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K09690
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: NAGANO Seiichi 大阪大学, 医学系研究科, 准教授 (40362727)
• Co-Investigator(Kenkyū-buntansha): 永井 義隆 大阪大学, 医学系研究科, 寄附講座教授 (60335354)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: TDP-43 / 軸索輸送 / 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / リボソーム蛋白質 / 局所翻訳

Outline of Final Research Achievements

In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), abnormal deposition of the RNA-binding protein TDP-43 in neurons was observed, suggesting a relationship with the pathogenesis. We hypothesized that impairment of TDP-43-mediated mRNA transport to neuronal axons would cause ALS/FTLD, and identified ribosomal protein (Rp) mRNA as its target. It was suggested that Rp mRNA is transported by binding and colocalizing with TDP-43 in axons, and the transported Rp mRNA is locally translated in axons and assembled into endogenous ribosomes. In the axons in which TDP-43 was down-regulated, local translational ability by ribosomes and axonal outgrowth was impaired, while the disturbance was ameliorated by overexpression of each Rp.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症（ALS）、前頭側頭葉変性症（FTLD）は根本的治療法のない重篤な神経変性疾患であり、一刻も早い効果的治療法の開発が切望されている。ALS/FTLDではRNA結合蛋白質TDP-43の神経細胞での局在異常が知られているが、我々は独自に開発した神経細胞区画培養法を用いて神経軸索を選択的に解析する手法を確立し、それによりTDP-43による軸索輸送標的としてリボソーム蛋白質（Rp）mRNAを同定した。Rp mRNAの発現を増加させる薬剤により、ALS/FTLDの新たな治療法が開発されることが期待される。