Study of pathogenic mechanism of amyotrophic lateral sclerosis through excessive recrutiment of RNA-binding protein FUS

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16489
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Nagoya University
• Principal Investigator: Yokoi Satoshi 名古屋大学, 医学系研究科, 特任助教 (30815460)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 筋萎縮性側索硬化症 / シナプス / アンチセンスオリゴ / iPS細胞由来運動神経

Outline of Final Research Achievements

In order to investigate whether the synaptic protein SynGAP could be pathogenic for amyotrophic lateral sclerosis(ALS), we found a novel variant in SynGAP 3'UTR from the JaCALS database. We inserted this variant into iPS cells and differenciated to motor neurons. We found that this variant causes splicing of SynGAP and a decrease in the number of synapses. Furthermore, FUS and hnRNPK are excessively recruited to SynGAP mRNA by this mutation. Antisense oligonucleotides whicht block hnRNPK binding site could recover the number of synapses. These data suggested that novel SynGAP variant causes early pathology of ALS, and excessive recrutiment of RNA-binding proteins could be a novel pathological mechanism of ALS.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

未だに発症原因が解明されていない筋萎縮性側索硬化症において、本研究はシナプスタンパク質が病態に関わっており、さらにRNA結合蛋白質の過結合がシナプス異常を引き起こすスプライシング異常にかかわっていることも初めて発見した。さらに過結合を是正するアンチセンスオリゴがシナプス異常を是正できた。これらの知見は、治療薬がない筋萎縮性側索硬化症の今後の治療薬開発において、ごく局所のRNA代謝異常をターゲットにする重要性が示唆された。