2020 Fiscal Year Final Research Report
Pathogenesis of ALS linked p62-mutants from the point of view of autophagy and oxidative stress
Project/Area Number |
18K07505
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52020:Neurology-related
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Research Institution | Kyoto Prefectural University of Medicine |
Principal Investigator |
Watanabe Yoshihisa 京都府立医科大学, 医学(系)研究科(研究院), 講師 (50363990)
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Co-Investigator(Kenkyū-buntansha) |
徳田 隆彦 京都府立医科大学, 医学(系)研究科(研究院), 教授 (80242692)
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Keywords | 筋委縮性硬化症 / 前頭側頭型認知症 / p62 / オートファジー / 酸化ストレス |
Outline of Final Research Achievements |
Mutations in a multifunctional adaptor protein p62 are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). p62 is implicated in selective autophagy and oxidative stress response. To investigate the pathogenic mechanism of ALS/FTD by p62 mutations, we produced the stable cell lines expressing p62-WT, P392L and G425R. Interestingly, both p62 mutants were cleaved at specific positions under stress conditions. Next, we assessed oxidative stress response via the p62-Keap1-Nrf2 axis in p62 mutant cells. Heme oxygenase-1 expression was significantly suppressed in both p62 mutant cells. Furthermore, p62 mutations decreased the binding of the UBA domain to ubiquitinated proteins. These results suggest that reduction of stress response and autophagic clearance of ubiquitinated proteins might be involved in the pathogenic mechanism of ALS/FTD by p62 mutations.
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Free Research Field |
神経内科
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Academic Significance and Societal Importance of the Research Achievements |
本研究では筋委縮性側索硬化症(ALS)/前頭側頭型認知症(FTD)の原因遺伝子の1つであるp62による疾患発症機序の研究を行った。ALS/FTD変異p62はストレスにより異常な切断を受け、酸化ストレス応答やオートファジーに障害を及ぼすことが明らかになった。今後、この異常切断を行うプロテアーゼを解明することで新たな治療法の開発につながる可能性がある。
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