French scientist discovers the cause of narcolepsy

HASNarcolepsy is possibly one of the strangest, most mysterious and devastating conditions in the disease department. Patients affected by it “suffer terribly.” The Frenchman Emmanuel Mignot has dedicated his career to the study of narcolepsy, until he found the cause and thus shed some light on one of the great mysteries of biology: sleep. The discovery of it, in the heart of the meanders of our brain, has today earned him the award with an important American prize, the Breakthrough Prize, together with the Japanese Masashi Yanagisawa, who reached similar conclusions at the same time.

Thanks to this research, drugs are now being developed that promise to revolutionize the treatment of narcolepsy and other sleep disorders. Narcoleptics, about one in 2,000 people, can’t help but suddenly fall asleep in the middle of the day. Some are also affected by sudden temporary paralysis (cataplexy). “I am very proud, because what I discovered is making a big difference for my patients. This is the best reward we can receive”, confides to Agence France-Presse this professor from Stanford University, in California, where narcoleptics from all over the world come to consult him.

Thirty years ago, a young medicine and science graduate, Emmanuel Mignot decided to travel to the United States during his military service, in order to study the operation of a drug then used against narcolepsy.

At the time, this disease was “practically unknown” and “nobody studied it,” he recalls. But he “was completely fascinated.” “I said to myself, this disease is incredible, people fall asleep all the time, we have no idea why, and if we could find the cause, we could understand something new about sleep,” explains the 63-year-old woman. investigator.

missing key

Stanford then has narcoleptic dogs and sets out to find the gene that causes the disease in them. A titanic undertaking, because genome sequencing techniques were primitive at the time. “Everyone told me he was crazy,” recalls Mignot, who now lives with a narcoleptic dog, Watson, whom he adopted. “I thought he was going to take a few years, and he took 10 years. Finally, in 1999, the discovery: a receptor located in the brain cells of narcoleptic dogs is abnormal.

This receptor is like a lock, which only reacts in the presence of the correct key: a molecule discovered at the same time by the Japanese Masashi Yanagisawa, who named it orexin (also sometimes called hypocretin). It is a neurotransmitter produced in the hypothalamus, at the base of the brain, by a very small population of neurons. Immediately, Emmanuel Mignot carried out the first tests on humans. And the results are impressive: orexin levels in the brains of narcoleptic patients are zero.

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However, in normal times, this molecule is produced in large quantities throughout the day, especially at night, which makes it possible to fight against accumulated fatigue. The path of action of the disease is therefore similar: in dogs, the lock is broken, but in humans, the key is missing. Which also explains why the disease can be inherited in dogs, not humans. “You don’t make a discovery like that twice in your life. We found the cause of a disease”, marvels the Frenchman. “The advantage is that the key, we can remake it. »

“miraculous” treatment

At the moment, most patients are treated with a combination of anesthetics to put them into a deep sleep at night and amphetamines to wake them up during the day. But by administering a drug that mimics orexin in trials, the results are “truly miraculous,” says Mignot. The patients then have “other eyes”, they are “only awake, calm”, a true “transformation”. »

The current challenge remains to develop the formulation that provides the right dose at the right time. Several companies, including Japan’s Takeda, are working on the issue, and the drugs could be licensed in the next few years. Applications for other diseases are also possible: for example, for depressed patients who have difficulty getting up or in a coma and difficulty waking up, says the researcher.

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Not all questions are answered. Emmanuel Mignot is now trying to prove that narcolepsy is caused by the flu virus. According to him, the immune system, which is responsible for defending us against infections, can begin to confuse orexin-producing neurons with certain flu viruses, and end up attacking them. However, once dead, these neurons cannot be renewed and patients will no longer be able to produce orexin for life.

More broadly, “I became interested in how the immune system works in the brain,” he says, an “explosive” field. Quant au mystère du sommeil, même s’il en elucidé l’un des grands mécanismes, le chercheur s’avoue toujours fascinated : « What is the sommeil fait qui est si important qu’on a besoin de le faire every day ? He asks. “It is true that we still do not understand. »

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