Molecular pathogenesis of Rett syndrome by brain immune cells via endogenous DNA ligands

2024 Fiscal Year Final Research Report

• Project/Area Number: 22K15201
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Kyushu University
• Principal Investigator: Nakashima Hideyuki 九州大学, 医学研究院, 助教 (00835390)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Keywords: レット症候群 / MeCP2 / レトロトランスポゾン / ミクログリア

Outline of Final Research Achievements

Mutations in the MECP2 gene have been implicated in a variety of neuropsychiatric and developmental disorders, including Rett syndrome (RTT) and autism, although the precise mechanisms underlying these conditions remain unclear.In this study, we tested the hypothesis that aberrant activation of glial cells is induced by cDNA derived from the retrotransposon LINE-1 (L1). To evaluate this, we performed behavioral assessments in MECP2-KO mice and conducted a comprehensive analysis to identify functional molecules involved in glial cell activity.As a result, we found that inhibiting the production of L1-cDNA ameliorated RTT-like behavioral phenotypes in MeCP2-KO mice. Furthermore, inhibition of L1- cDNA production also improved the aberrant activation of glial cells and neuronal morphological abnormalities.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

MeCP2はその発見の経緯からメチル化DNA結合性の転写抑制因子として考えられ、DNAメチル化と精神疾患・神経発達障害を結びつける分子として世界中で研究が行われてきた。しかしながら、RTT患者やMeCP2欠損マウス脳を用いたトランスクリプトーム解析では、転写レベルにおける有意な遺伝子発現変化は確認されておらず、RTTの特徴的な表現型と直接結びつくような標的遺伝子の発現異常は現在までに明らかとなっていない。そのため、レトロトランスポゾン由来cDNAに着目した本研究成果は、RTTの新規な分子病態理解につながると同時に、治療法開発においても重要な手がかりとなる可能性が高い。