A key mechanism of narcolepsy deciphered

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(Image Depositphotos)
(Image Depositphotos)

A recent study is shaking up what is known about this condition, which is considered incurable, and could lead to a treatment. Orexin (also called hypocretin, or HCRT) is one of the most versatile neurotransmitters in the brain. It plays a role in motivation, energy metabolism and sleep/wake rhythms. The absence of HCRT leads to a profound disorganization of alertness states, difficulty staying awake during the day and falling asleep at night, as well as sudden paralysis (loss of muscle tone) in moments of intense emotional excitement. The latter is called narcolepsy with cataplexy. The disease appears during childhood or early adulthood: it is still incurable.

HCRT deficiency is generally thought to result from neurodegeneration of the few thousand nerve cells located in the center of the brain, in the hypothalamus, that produce this peptide. A team led by Mehdi Tafti, a full professor at the Faculty of Biology and Medicine (FBM) at UNIL, has proposed and tested a bold new hypothesis: what if HCRT deficiency is not due to the death of the cells, but to the fact that the marker we use to detect them is silenced - in other words, what if the HCRT gene is silent but the neurons are still present?

This is what an article published in the Proceedings of the National Academy of Sciences ( PNAS ), of which Ali Seifinejad, associate researcher in Prof. Tafti’s group, is the first author, attempts to show. By analyzing post-mortem brain tissue from patients, the researchers were able to identify a new marker of HCRT neurons, a neuropeptide called QRFP, and show that it was still expressed. In addition, the scientists discovered a mechanism that would explain the silencing of the HCRT gene: they found, again from post-mortem brain tissue of patients with narcolepsy, that the DNA promoter of the HCRT gene was hypermethylated, a modification known to repress gene expression.

Towards new therapeutic approaches?

The researchers also showed that narcolepsy does not exclusively affect HCRT neurons, but that the same mechanism affects several other genes coding for neuropeptides, also expressed in the hypothalamus and previously thought to be lost through cell death.

If you are diagnosed with narcolepsy, sleep specialists will tell you that it is for life, that you have lost these cells in your brain, explains Mehdi Tafti. But this study shows that people with narcolepsy have not lost these neurons; instead, they have stopped producing the neuropeptide! We are convinced that the neurons are still there’, adds the professor at the Department of Biomedical Sciences of the BMF.

This study could have profound ramifications for patients and the pharmaceutical industry: if HCRT neurons are not dead, but only silenced, the discovery opens the door to therapies to reactivate these silent genes, since DNA methylation is reversible. DNA methylation is one of the mechanisms grouped under the generic banner of epigenetics, and suspected of being involved in other neurological diseases. In other words, this study brings hope for patients with narcolepsy and for the understanding of several other neurodegenerative diseases.