Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy.

Autor: Seifinejad A; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Ramosaj M; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Shan L; Sleep-Wake Centre Stichting Epilepsie Instellingen Nederland, 2103SW Heemstede, The Netherlands.; Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands.; Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam 1105 BA, The Netherlands., Li S; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Possovre ML; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Pfister C; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Fronczek R; Sleep-Wake Centre Stichting Epilepsie Instellingen Nederland, 2103SW Heemstede, The Netherlands.; Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands., Garrett-Sinha LA; Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14260-1660., Frieser D; Infinity-Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, CNRS, INSERM, Université Paul Sabatier, 31059 Toulouse, France., Honda M; Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, 156-8506 Tokyo, Japan.; Institute of Neuropsychiatry, Seiwa Hospital, 162-0851, Tokyo, Japan., Arribat Y; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Grepper D; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Amati F; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Picot M; Normandie Univ, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, 76000 Rouen, France., Agnoletto A; Institut Suisse de Recherche Expérimentale sur le Cancer, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland., Iseli C; Bioinformatic Competence Center, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland., Chartrel N; Normandie Univ, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, 76000 Rouen, France., Liblau R; Infinity-Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, CNRS, INSERM, Université Paul Sabatier, 31059 Toulouse, France., Lammers GJ; Sleep-Wake Centre Stichting Epilepsie Instellingen Nederland, 2103SW Heemstede, The Netherlands.; Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands., Vassalli A; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland., Tafti M; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 May 09; Vol. 120 (19), pp. e2220911120. Date of Electronic Publication: 2023 May 01.
DOI: 10.1073/pnas.2220911120
Abstrakt: 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.
Databáze: MEDLINE
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