Pathophysiology of non-coding repeat expansion disorders

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17043
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• 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)
• Project Period (FY): 2019-04-01 – 2022-03-31
• 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.

Free Research Field

神経

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。