2021 Fiscal Year Final Research Report

Pathophysiological analysis of repeat disease causing neurodegenerative disease using human brain organoids.

Research Project

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Project/Area Number	19K07978
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	Nara Medical University
Principal Investigator	Kiriyama Takao 奈良県立医科大学, 医学部, 講師 (80571025)
Co-Investigator(Kenkyū-buntansha)	杉江和馬奈良県立医科大学, 医学部, 教授 (60347549) 松井健島根大学, 学術研究院医学・看護学系, 特任講師 (90528605) 七浦仁紀奈良県立医科大学, 医学部, 助教 (00827909) 塩田智奈良県立医科大学, 医学部附属病院, 研究員 (70837062) 井口直彦奈良県立医科大学, 医学部附属病院, 研究員 (50838232)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	神経変性疾患 / 非翻訳領域リピート病 / 筋萎縮性側索硬化症 / 脳オルガノイド / FUS / C9orf72
Outline of Final Research Achievements	The pathogenesis of neurodegenerative diseases associated with non-coding repeat expansion remains unclear. In this study, we generated brainstem organoids from human pluripotent stem cells that can be used in disease models and elucidated their characteristics and gene expression responses under stress. We also investigated and visualized the function of FUS, the causative gene of ALS, as a DNA repair protein. we also showed that polypeptides produced from non-coding repeat expansion of C9orf72 disrupt the phase separation regulatory ability of Kapβ2, a nuclear transport receptor. In addition, we found that polypeptides bind to intermediate filaments and enhance cell stiffness, inhibit cell detachment, and exacerbate the mechanical stress response.
Free Research Field	神経内科学
Academic Significance and Societal Importance of the Research Achievements	本研究の結果から、非翻訳領域リピート病において毒性ポリペプチドが細胞機能障害を起こす病態メカニズムの一部が明らかとなった。また独自のプロトコールによる脳幹オルガノイドの特性を明らかにした。今後のオルガノイドの神経変性疾患モデルとして利用や、さらなる病態解明、治療法の開発へも寄与することが期待される。