Analysis of the molecular link of amyotrophic lateral sclerosis associated genes in sporadic ALS model mice

2015 Fiscal Year Final Research Report

• Project/Area Number: 25461269
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: Yamashita Takenari 東京大学, 医学(系)研究科(研究院), 特任研究員 (20431843)
• Co-Investigator(Renkei-kenkyūsha): KWAK Shin 東京大学, 大学院医学系研究科, 客員研究員 (40160981)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 筋萎縮性側索硬化症 / カルパイン / RNA編集 / カルシウム / TDP-43 / ADAR2 / AMPA受容体 / リン酸化

Outline of Final Research Achievements

We found that ADAR2-negative motor neurons in the spinal cord showed TDP-43 pathology, or subcellular mislocalization of TDP-43, in the conditional ADAR2 knockout (AR2) mice, a mechanistic ALS model in which the ADAR2 gene was targeted in cholinergic neurons including motor neurons. TDP-43 pathology in the ADAR2-lacking motor neurons in the AR2 mice was caused by abnormal activation of calpain, a Ca2+-dependent cysteine protease. We revealed several calpain-dependent cleavage sites in the C-terminal region of TDP-43. Moreover, we found that phosphorylated full-length TDP-43 and calpain-dependent TDP-43 fragments were more resistant to cleavage by calpain than endogenous full-length TDP-43 was.

Free Research Field

内科系臨床医学・神経内科学