Elucidation of the mechanism of neurodegeneration in narcolepsy by cross-tissue genome-wide methylation analysis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15053
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: The University of Tokyo (2019-2020); Tokyo Metropolitan Institute of Medical Science (2018)
• Principal Investigator: Shimada Mihoko 東京大学, 大学院医学系研究科(医学部), 助教 (50792727)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ナルコレプシー / DNAメチル化

Outline of Final Research Achievements

In this study, we examined DNA methylation in narcolepsy in multiple brain regions, including the posterior hypothalamus, where orexin neural loss occurs,　and in CD4 and CD8 positive T cells, which may contribute to the disease. The disease-associated DNA methylation sites in the brain were specific to the posterior hypothalamus, and the associated sites overlapped significantly with previously reported multiple sclerosis-associated methylation sites. In the analysis with T cells, in addition to the association of methylated regions upstream of immune-related genes, a large difference in methylation rates between patients and healthy controls was found, especially for CD4-positive T cells, with over 95% of disease-associated methylation sites having reduced methylation rates in patients. These CpGs hypomethylated in narcolepsy were significantly less common in CpG Island, shore and promoter regions.

Free Research Field

人類遺伝学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果から、脳の解析ではナルコレプシー関連メチル化部位は後部視床下部特異的にみられ、多発性硬化症の関連メチル化部位と有意に重複することから、後部視床下部における免疫的機序の異常が疾患発症に関わる可能性が、DNAメチル化という観点からも示唆された。さらにナルコレプシーのCD4及びCD8陽性Ｔ細胞の双方において、メチル化率の低下傾向が観察された。ナルコレプシーと関連を示す遺伝子多型がDNAメチル化酵素であるDNMT1の上流領域に位置していることが報告されており、今後DNMT1の発現や全体的な低メチル化が与える影響についてより詳細に解析することで、発症メカニズムの解明につながる可能性がある。