Analysis of novel transcription factors for hypocretin and involvement of narcolepsy

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08533
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: Kansai Medical University
• Principal Investigator: TANAKA Susumu 関西医科大学, 医学部, 准教授 (30399472)
• Research Collaborator: KODAMA Tohru
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: オレキシン / 睡眠 / 覚醒 / PLAGL1

Outline of Final Research Achievements

The hypocretin/orexin neuropeptide coordinates the regulation of various physiological processes. Our previous study suggested that PLAGL1 is coexpressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro-hypocretin transcription is functionally modulated by PLAGL1.
The majority of hypocretin neurons were positive for PLAGL1 in the nucleus. Notably, PLAGL1 in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detectedfollowing sleep deprivation. ChiP-PCR revealed that endogenous PLAGL1 may bind to a putative PLAGL1 binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription.
These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.

Free Research Field

睡眠科学

Academic Significance and Societal Importance of the Research Achievements

本研究により見いだされたオレキシン転写制御因子を用いることにより、ある程度オレキシンニューロンへの分化が決定した幹細胞のオレキシン発現を安定させられると考えられる。それはナルコレプシーの根本治療へとつながっていく。さらにオレキシンニューロン数を安定させることにより、ナルコレプシー患者血清ならびに脳脊髄液中に存在すると考えられているオレキシンニューロン脱落因子の探索を可能とし、ひいてはナルコレプシーの病態解明につながっていく。