French scientist discovers the cause of narcolepsy

HASnarcolepsy is arguably one of the most bizarre, mysterious, and devastating conditions in the disease department. Patients affected by it “suffer terribly”. Frenchman Emmanuel Mignot has devoted 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. His discovery, at the heart of the meanders of our brain, has earned him the award today with a major American prize, the Breakthrough Prize, alongside the Japanese Masashi Yanagisawa, who came to similar conclusions at the same time.

Thanks to this research, drugs that promise to revolutionize the treatment of narcolepsy and other sleep disorders are now being developed. 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’m quite proud, because what I discovered is making a huge difference for my patients. This is the best reward we can receive, ”confides to Agence France-Presse this professor at Stanford University, in California, where narcoleptics from all over the world come to consult him.

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

At the time, this disease was “virtually unknown” and “no one was studying it”, he recalls. But he “became 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 of it, we could understand something new about sleep” , explains the 63-year-old researcher.

Missing key

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

This receptor is like a lock, which only reacts in the presence of the right key: a molecule, discovered at the same time by the Japanese Masashi Yanagisawa, who baptized 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 in humans. And the results are breathtaking: 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 in the evening, making 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 find the cause of a disease,” marvels the Frenchman. “The advantage is that the key, we can redo it. »

“miraculous” treatment

For the moment, most patients are treated with a combination of anesthetics to make them sleep soundly at night, and amphetamines to wake them up during the day. But by giving an orexin-mimicking drug in trials, the results are “truly miraculous,” says Mignot. The patients then have “different eyes”, they are “just awake, calm”, a real “transformation. »

The challenge today remains to develop the formulation delivering the right dose at the right time. Several companies, including the Japanese Takeda, are working on the subject, and drugs could be authorized in the coming years. Applications for other diseases are also possible: for example, for depressed patients who have difficulty getting up or in a coma and difficult to wake up, says the researcher.

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

More broadly, “I started to take an interest in how the immune system works in the brain”, he says, a field “exploding”. As for the mystery of sleep, even if he has elucidated one of its major mechanisms, the researcher still admits to being fascinated: “What does sleep do that is so important that we need to do it? every day ? he wonders. “It’s true that we still don’t understand. »

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