After a lifetime of research, a Frenchman has been rewarded for finding the cause of narcolepsy

It’s an illness “strange”, “incredible”, but also “destructive”including patients with “suffer terribly”. Frenchman Emmanuel Mignot devoted his career to studying narcolepsy until he found the cause and shed some light on one of the great mysteries of biology: sleep.

drugs in development

Today, his discovery at the heart of the meanders of our brain has earned him a prestigious American prize, the Breakthrough Prize, alongside the Japanese Masashi Yanagisawa, who came to 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 quite proud because what I have discovered is making a huge difference to my patients. It’s the best reward you can get.” AFP entrusts this professor at Stanford University in California, where narcoleptics from all over the world consult him.

30 years ago, Emmanuel Mignot, a young graduate student in medicine and science, decided to go to the United States while serving in the military to study the effects of a drug then used to treat narcolepsy.

At that time was this disease “virtually unknown” and “Nobody has studied it” he remembers. But he is “was totally fascinated”.

“I said to myself, this disease is amazing, 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.

key is missing

Stanford then has narcoleptic dogs and sets out to find the gene that causes the disease in them.

A titanic undertaking, since genome sequencing techniques were primitive at the time. “Everyone told me I was crazy” remembers Mr. Mignot, who is now living with a narcoleptic dog named Watson, whom he adopted. “I thought it would take a couple of years, and it took 10 years. »

Finally, in 1999, the finding: a receptor located on the brain cells of narcoleptic dogs is abnormal.

This receptor is like a lock that only reacts in the presence of the right key: a molecule discovered at the same time by the Japanese Masashi Yanagisawa, who named it orexin (sometimes called hypocretin). It is a neurotransmitter produced in the hypothalamus at the base of the brain by a very small population of neurons.

Emmanuel Mignot immediately carried out the first tests on humans. And the results are stunning: Orexin levels in the brains of narcoleptics are zero.

In normal times, however, this molecule is produced in large quantities throughout the day, especially in the evening, which makes it possible to fight against accumulated fatigue.

The path of action of the disease is therefore similar: in dogs, the lock has been broken, in humans the key is missing. This also explains why the disease can be inherited in dogs, not humans.

“You don’t make a discovery like this twice in your life. We find the cause of a disease, marvels the Frenchman. “The advantage is that we can repeat the key. »

“Wonderful” treatment

Currently, most patients are treated with a combination of anesthetics to help 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 “really wonderful”, says Mr. Mignot. patients then have “other eyes” they are “just awake, calm”, a real “Transformation. »

The challenge today remains to develop the formulation that delivers the right dose at the right time. Several companies, including Japan’s Takeda, are working on the issue, and drugs could be approved in the coming years.

Applications for other diseases are also possible: for example, in depressed patients who have difficulty getting up or who are in a coma and find it difficult to wake up, says the researcher.

Not all questions will be 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 fighting off infection, can start to mistake the neurons that produce orexin for certain flu viruses and eventually attack them. However, once these neurons are dead, they can no longer be renewed, and patients will be unable to produce orexin for the rest of their lives.

wider, “I became interested in how the immune system works in the brain”he says, a domain “exploded”.

As for the mystery of sleep, the researcher admits that he’s still fascinated even though he’s elucidated one of its main mechanisms: “What makes sleep so important that we need to do it every day? »he wonders. “It is true that we still do not understand. »

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