Elucidation of the pathogenesis of genetic encephalopathy caused by defects in RNA editing

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07080
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Osaka University
• Principal Investigator: Nakahama Taisuke 大阪大学, 大学院医学系研究科, 助教 (10636187)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: RNA編集 / ADAR1 / AGS / 脳症 / MDA5

Outline of Final Research Achievements

Mutations in the RNA-editing enzyme ADAR1 cause Aicardi-Goutieres syndrome (AGS), which is characterized by interferon (IFN) overproduction and encephalopathy. To date, no model recapitulates AGS encephalopathy, and thus its pathogenesis is not fully understood. In this study, we found that AGS knock-in (KI) mice carrying an AGS-associated K948N point mutation in the Adar1 gene reproduce AGS-like encephalopathy with activation of the RNA sensor MDA5. In addition, the pathological abnormalities found in AGS KI mice were ameliorated by the sole expression of ADAR1 p150, an isoform of ADAR1. Therefore, we comprehensively identified the ADAR1 p150-specific editing sites as potential substrates for MDA5.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

現状ではAGSの治療法は未確立であり、病態解明が急務であるが、これまでAGS症状を再現するモデル動物は確立されていなかった。本研究では、新規に樹立したAdar1遺伝子点変異マウスが、MDA5活性化に起因する脳症を示すことを明らかにした。このため、本マウスを用いることによってAGS病態の解明のみならず、新規治療候補の評価にも活用されることが期待される。