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論文
- タイトル
- タイトル（英）
- Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy
- 参照URL
- https://researchmap.jp/narcolepsy/published_papers/42760536
- 著者
- 著者（英）
- Ali Seifinejad,Mergim Ramosaj,Ling Shan,Sha Li,Marie-Laure Possovre,Corinne Pfister,Rolf Fronczek,Lee A. Garrett-Sinha,David Frieser,Makoto Honda,Yoan Arribat,Dogan Grepper,Francesca Amati,Marie Picot,Andrea Agnoletto,Christian Iseli,Nicolas Chartrel,Roland Liblau,Gert J. Lammers,Anne Vassalli,Mehdi Tafti
- 担当区分
- 概要
- 概要（英）
- Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt,Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin ( PDYN ) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT , PDYN , and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.
- 出版者・発行元
- 出版者・発行元（英）
- Proceedings of the National Academy of Sciences
- 誌名
- 誌名（英）
- Proceedings of the National Academy of Sciences
- 巻
- 120
- 号
- 19
- 開始ページ
- 終了ページ
- 出版年月
- 2023年5月9日
- 査読の有無
- 査読有り
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- 0027-8424
- DOI URL
- https://doi.org/10.1073/pnas.2220911120
- 共同研究・競争的資金等の研究課題
研究者
本多 真
(ホンダ マコト)