2021 Fiscal Year Final Research Report
Pathophysiology of non-coding repeat expansion disorders
Project/Area Number |
19K17043
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 52020:Neurology-related
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Research Institution | Nara Medical University |
Principal Investigator |
Shiota Tomo 奈良県立医科大学, 医学部附属病院, 研究員 (70837062)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | ALS |
Outline of Final Research Achievements |
Proline:arginine (PR) poly-dipeptides from the GGGGCC repeat expansion in C9orf72 have cytotoxicity and bind intermediate filaments (IFs). However, it remains unknown how PR poly-dipeptides affect the cytoskeletal organization and focal adhesion (FA) formation. Here, we show that the changes of cytoskeleton and FA by PR poly-dipeptides result in the alteration of cell stiffness and mechanical stress response. PR poly-dipeptides increased the junctions and branches of the IF network, increased cell stiffness, changed the distribution of actin filaments and increased the size of FA. In addition, PR poly-dipeptides or an inhibitor of IF organization prevented the cell detachment. Furthermore, PR poly-dipeptides upregulated mechanical stress response factors and led to a maladaptive response to cyclic stretch. These results suggest that the effects of PR poly-dipeptides on mechanical properties and mechanical stress response may serve as a pathogenesis of C9orf72-related neurodegeneration.
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Free Research Field |
神経
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Academic Significance and Societal Importance of the Research Achievements |
細胞の機械的特性や機械的ストレス応答は、細胞の恒常性に関与し重要である。しかし、筋萎縮性側索硬化症(ALS)においてこれらがどのように変化しているか不明であった。本研究は、細胞の表面の硬さの変化や機械的ストレス応答の変化が、ALSの病態に関与する可能性があることを始めて明らかにしたもので、ALSの病態解明の一助になると考えられる。
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