Exploration of pathogenesis for upper motor neuron dysfunction of sporadic ALS employing sporadic ALS model mice

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07967
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Hideyama Takuto 東京医科大学, 医学部, 講師 (30511456)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 筋萎縮性側索硬化症 / ALS / RNA編集 / GluA2 / ADAR2 / 上位運動ニューロン / TDP-43 / ノックアウトマウス

Outline of Final Research Achievements

ALS is a common neurodegenerative disease of unknown etiology of upper motor neurons (UMNs) dysfunction. ADAR2 mediated RNA editing of GluA2 mRNA at the Q/R site was commonly deficient in the LMNs of ALS. We have developed genetically modified mice (AR2 mice) in that the ADAR2 gene is selectively knocked out in cholinergic neurons. AR2 mice indicated progressive loss of LMNs. However, the changes of UMNs in AR2 mice is unknown. We investigated whether similar degeneration is observed in UMNs of AR2 mice. We compared the number of pathological TDP-43 and the morphology of large neurons in primary (M1) and secondary motor cortex (M2) of AR2 mice with age-matched wild-type mice. TDP-43 pathology in AR2 mice is observed with lacking ADAR2 immunoactivity. The number of large neurons with TDP-43 pathology was significant increased both in M1 and M2 of AR2 mice. These results indicate that deficient ADAR2 activity is likely involved in TDP-43 pathology of UMNs of AR2 mice.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究では，孤発性ALS同様にTDP-43病理が，AR2マウスの大脳皮質の神経細胞において神経変性と共に認められた．AR２マウスは上位運動ニューロン障害の検討においても孤発性ALSのモデルとして有用と考えられ，これまでの成果と合わせると孤発性ALSにおいて上位運動ニューロンと下位運動ニューロンの変性が同様の経路を介して生じている可能性が高いと考えられた．AR２マウスを利用し，ペランパネルの有用性が得られ，さらに有効かつ安全性の高い薬剤，遺伝子治療をはじめとした治療法の開発が進められている. 今後も本研究の継続で変性疾患の病因解明と発症メカニズムに基づいた分子標的治療法の開発が期待できる．