Résumé
SignificanceNarcolepsy with cataplexy is characterized by excessive daytime sleepiness and sudden loss of muscle tone (cataplexy) triggered by strong emotions. The best marker of the disease is low/absent hypocretin (HCRT), a hypothalamic neuropeptide. An autoimmune attack targeting these neurons is believed to cause HCRT deficiency, despite any direct evidence. We demonstrate that a substantial number of HCRT neurons are present in the brain of patients, but HCRT gene is silenced by methylation. The epigenetic silencing is not restricted to HCRT but also CRH and PDYN genes are methylated in the hypothalamus of patients. Our results strongly suggest that HCRT and CRH neurons are not destroyed but epigenetically deactivated, and possibilities exist to reactivate them to treat or even cure narcolepsy.
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.