Pathogenesis of TDP-43 proteinopathy based on the transport defect of target mRNA

2015 Fiscal Year Final Research Report

• Project/Area Number: 25461302
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Nagano Seiichi 国立研究開発法人国立精神・神経医療研究センター, 神経研究所疾病研究第五部, 室長 (40362727)
• Co-Investigator(Renkei-kenkyūsha): NAGAI Yoshitaka 大阪大学, 大学院医学系研究科神経難病認知症探索治療学寄附講座, 教授 (60335354)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: TDP-43 / mRNA / 神経突起輸送 / 筋萎縮性側索硬化症 / 前頭側頭葉変性症

Outline of Final Research Achievements

Abnormal deposition of an RNA-binding protein TDP-43 is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). We hypothesized that mRNA transport to neurites by TDP-43 is disturbed by deposition of the protein and failure of a specific mRNA transport is associated with ALS/FTLD-U pathogenesis, and identified mRNA of ribosomal proteins (Rp) as targets for TDP-43-mediated transport. We have proven in this study that Rp mRNA binds TDP-43 through its untranslated region and co-localizes with the protein in neurites. Down-regulation of TDP-43 expression disrupted neuritic extension and local ribosomal function. Moreover, exogenously introduced Rp was assembled into endogenous ribosomes.

Free Research Field

神経内科学