TY - JOUR T1 - Narcolepsy with cataplexy is caused by epigenetic silencing of hypocretin neurons JF - bioRxiv DO - 10.1101/2021.09.21.461046 SP - 2021.09.21.461046 AU - Ali Seifinejad AU - Almar Neiteler AU - Sha Li AU - Corinne Pfister AU - Rolf Fronczek AU - Ling Shan AU - Lee A. Garrett-Sinha AU - David Frieser AU - Makoto Honda AU - Yoan Arribat AU - Dogan Grepper AU - Francesca Amati AU - Marie Picot AU - Christian Iseli AU - Nicolas Chartrel AU - Gert J. Lammers AU - Roland Liblau AU - Anne Vassalli AU - Mehdi Tafti Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/09/24/2021.09.21.461046.abstract N2 - Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The condition is believed to result from autoimmune destruction of hypocretin (HCRT) neurons, although direct evidence is lacking and mere Hcrt gene inactivation causes full-blown narcolepsy in mice. Here we show that the expression of another hypothalamic neuropeptide, QRFP, is lost in mouse models with HCRT cell-ablation, but tends to be even increased in Hcrt gene knockout mice, suggesting that QRFP expression can be used as a proxy for the presence or absence of HCRT neurons. Similar to Hcrt knockout mice, narcolepsy patients show intact hypothalamic QRFP expression, and cerebrospinal fluid levels of QRFP peptide are increased, suggesting their HCRT neurons are intact. We show that the human HCRT gene promoter is methylation-sensitive in vitro, and is hypermethylated in the hypothalamus of patients selectively at a putative PAX5:ETS1 binding site within the proximal HCRT promoter. Ets1-KO mice display downregulated Hcrt expression, while pax5-ets1 knockdown in zebrafish causes decreased hcrt expression, decreased activity and sleep fragmentation, similar to narcolepsy patients. Our results suggest that HCRT neurons are alive, but epigenetically silenced, in the hypothalamus of narcolepsy patients, opening the possibility to reverse or cure narcolepsy.Competing Interest StatementM.T.: Consulting for NLS Pharmaceutics and unrestricted research grant from Jazz Pharmaceuticals. G.J.L.: Consulting for Jazz, UCB, Bioprojet and NLS Pharmaceutics, and member of advisory board Jazz, UCB, Bioprojet. F.R.: Consulting for Bioprojet. M.H.: Consulting for Takeda Phamaceutical Company, Ono Pharmaceutical and Alfresa Pharma Corporation. All other authors declare no competing interests. ER -