Molecular mechanism of conformational alteration in SOD1 and its disruption in the pathogenesis of ALS

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15358
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: The University of Tokyo
• Principal Investigator: Fujisawa Takao 東京大学, 大学院薬学系研究科(薬学部), 助教 (50636644)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: ALS / SOD1

Outline of Final Research Achievements

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no cure. SOD1, one of the causative genes in familial ALS, is structurally altered by ALS-linked genetic mutation and exerts cytotoxicity. We have previously reported that wild-type SOD1 (SOD1 WT) also adopts a mutant-like conformation under stress conditions, but the detailed molecular mechanism and its involvement in ALS have not been clarified. In this study, we focused on mutant-like SOD1 and performed comprehensive studies on its subcellular localization, binding factors, post-translational modifications, and degradation systems. We elucidated the molecular basis of conformational alteration in SOD1 WT under stress conditions.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

変異型SOD1がALSの原因になることはよく知られているが、ストレス条件下で変異型様に構造が変化した野生型SOD1のALSへの関与ついては不明な点が多い。本研究で明らかにした野生型SOD1の構造変化の分子基盤に関する基礎的知見は、SOD1遺伝子変異によらない家族性ALSおよび孤発性ALSにおけるSOD1の病態生理学的意義の解明や創薬ターゲットの発見につながると期待される。