Common pathogenesis in a wide-range of FTLD spectrum including ALS/FTLD and tauopathies

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K07367
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Nagoya University
• Principal Investigator: Ishigaki Shinsuke 名古屋大学, 医学系研究科, 特任准教授 (40378170)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 前頭側頭葉変性症 / 筋萎縮性側索硬化症 / FUS / SFPQ / タウ / タウオパチー / 進行性核上性麻痺 / 大脳皮質基底核変性症

Outline of Final Research Achievements

Immunofluorescent imaging showed impaired intranuclear colocalization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, PSP, and CBD patients, but not in AD and PiD patients. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and PSP patients, but not in those with AD. Furthermore, the mRNA ratio of 4R/3R-tau was elevated in patients with ALS/FTLD-TDP and PSP, but was largely unaffected in patients with AD. Lastly, considerable variation was observed in the expression of FUS and SFPQ within the neuronal nuclei of patients with ALS/FTLD-FUS, ALS/FTLD-TDP, PSP, and CBD, but was absent in those with AD or PiD.

Free Research Field

神経内科、病態神経科学

Academic Significance and Societal Importance of the Research Achievements

FUS・SFPQの神経細胞核内における微小局在は広義のFTLD疾患スペクトラムにおいて障害されていることが明らかになったことから、これまでスペクトラムを形成するものの病態機序が不明であったALS, FTLD, PSP, CBDといった疾患に共通のメカニズムが存在していることが示唆され、こうした知見をもとに疾患修飾薬の開発を進めることを可能にした。