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

Research Project

Project/Area Number 18K15053
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionThe 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
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywordsナルコレプシー / DNAメチル化 / CD4+ T細胞 / CD8+ T細胞 / 後部視床下部 / 過眠症 / 免疫系
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.

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。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (6 results)

All 2020 2019

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (4 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Epigenome-wide association study of narcolepsy-affected lateral hypothalamic brains, and overlapping DNA methylation profiles between narcolepsy and multiple sclerosis2020

    • Author(s)
      Shimada M, Miyagawa T, Takeshima A, Kakita A, Toyoda H, Niizato K, Oshima K, Tokunaga K, Honda M
    • Journal Title

      Sleep

      Volume: 43 Issue: 1

    • DOI

      10.1093/sleep/zsz198

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Metabolome Analysis Using Cerebrospinal Fluid From Narcolepsy Type 1 Patients2020

    • Author(s)
      Mihoko Shimada, Taku Miyagawa, Tohru Kodama, Hiromi Toyoda, Katsushi Tokunaga, Makoto Honda
    • Journal Title

      Sleep

      Volume: 未定 Issue: 11

    • DOI

      10.1093/sleep/zsaa095

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] EWAS of narcolepsy-affected lateral hypothalamic brain and overlapping methylation profile between narcolepsy and multiple sclerosis2019

    • Author(s)
      Mihoko Shimada, Taku Miyagawa, Katsushi Tokunaga, Makoto Honda
    • Organizer
      国際ゲノム会議
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 後部視床下部と側頭葉皮質サンプルを用いたナルコレプシーに関連するDNAメチル化の探索2019

    • Author(s)
      嶋多美穂子
    • Organizer
      日本睡眠学会第44回定期学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] DNA methylation profile of narcolepsy-affected brain and overlapping methylation profile between narcolepsy and multiple sclerosis2019

    • Author(s)
      Mihoko Shimada, Taku Miyagawa, Katsushi Tokunaga, Makoto Honda
    • Organizer
      アメリカ人類遺伝学会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 後部視床下部と側頭葉皮質サンプルを用いたナルコレプシーに関連するDNAメチル化の探索2019

    • Author(s)
      嶋多美穂子, 宮川卓, 本多真
    • Organizer
      日本睡眠学会第44回定期学術集会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2024-12-25  

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