Elucidation of the pathomechanism of neurodegeneration induced by TDP-43

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K08297
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Hashimoto Tadafumi 東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / TDP-43 / 神経変性疾患

Outline of Final Research Achievements

To elucidate the pathomechanism of TDP-43, we carried out RNA-seq analysis and found that Atg1 and several authophgic geneswere upregulated in the brain of TDP-43 transgenic (tg) fly. Knockdown of Atg1 rescued the retinal degeneration of TDP-43 tg fly, suggesting that autophagic pathway is involved in the pathogenesis of TDP-43. Moreover, we found that TDP-43 specifically intedacted with ULK1 mRNA in Neuro-2a cells and that knockdown of TDP-43 reduced the expression level of ULK1 protein, suggesting that TDP-43 regulates autophagic pathway via regulating the expression of ULK1.
By the analysis of the ALS-related genes, we found that overexpression of CREST induced neurodegeneration in the retina of tg fly, that familial ALS-linked mutations in Profilin1 cause the neurodegenetaion through the sequestration of TDP-43 into cytoplasm, and that self-assembly of FUS via its lox-complexity domain contributes neurodegeneration induced by FUS.

Free Research Field

神経生化学