Elucidation of disease mechanism of ALS/FTD using TDP-43vconditional knockout mice

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591258
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: TAKEUCHI Hideyuki 名古屋大学, 環境医学研究所, 助教 (30362213)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: TDP-43 / 神経変性疾患 / 筋萎縮性側索硬化症 / 前頭側頭葉型認知症

Outline of Final Research Achievements

TDP-43 has been linked to the pathophysiology of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTD/ALS). It is still open to debate whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function. Since TDP-43 is critical for embryonic development and fat metabolism, conventional knockout methods have failed to generate good models of TDP-43 “loss of function” model for FLD/ALS. To circumvent these problems, we developed the neuronal-specific, tamoxifen-inducible TDP-43 knockout mice. After ablation of TDP-43, mice exhibited behavioral abnormalities, cognitive dysfunction and rapid progressive motor paralysis associated with neuronal loss and massive gliosis, which resembles FTD/ALS phonotypes. This mouse model represents TDP-43 “loss of function” model for FTD/ALS. We propose that TDP-43 neurotoxicity is caused by a loss of its normal function.

Free Research Field

神経内科