Elucidating the pathogenesis of narcolepsy through metabolome and genome analyses and its application in personalized medicine

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H03588
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: MIYAGAWA Taku 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 副参事研究員 (20512263)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ナルコレプシー / ゲノム / 睡眠 / 過眠症 / アシルカルニチン / 脂肪酸代謝 / 人類遺伝学

Outline of Final Research Achievements

Metabolomic analysis was performed on cerebrospinal fluid (CSF) and blood from narcoleptic patients and controls; CSF-based metabolome analysis showed that histidine levels were significantly higher in the narcoleptic group than in the control group, while histamine levels were significantly lower in the narcoleptic group than in the control group. Blood-based metabolome analysis of acylcarnitine confirmed that the concentrations of several long-chain acylcarnitines were lower in the narcolepsy group, a difference that was statistically significant. Blood-based transcriptome analysis (RNA-seq) was performed and genes and pathways involved in carnitine shuttle and fatty acid metabolism were detected.

Free Research Field

人類遺伝学

Academic Significance and Societal Importance of the Research Achievements

ナルコレプシー患者では、CSF中のヒスチジン濃度が高いにもかかわらず、ヒスタミン濃度が低かった。このことから、ヒスチジンからヒスタミンへの合成が適切に行われていないことが示唆された。この結果は、ナルコレプシー治療薬（日本未承認）であるヒスタミンH3受容体拮抗薬/逆作動薬の薬理作用を間接的に支持するものである。血液サンプルを用いたアシルカルニチン解析及びRNA-seqの結果から、ナルコレプシーの病態生理に長鎖脂肪酸の代謝の機能低下が関わることが判明した。今後、このような血液中における代謝物や遺伝子発現の変動が、脳の睡眠中枢にどのような影響を与えているかを解明する必要がある。