We’re Taking the First Steps Toward a Cure for Narcolepsy
Back at Stanford, Mignot heard about the two papers, but there was no reason to imagine this new pathway had anything to do with narcolepsy or sleep. By the spring of 1999, however, he and his team had worked out that the recessive mutation had to lie in one of two genes. One was expressed in the foreskin. “It didn’t look like a candidate for narcolepsy,” says Mignot. The smart money was on the other gene, which encoded one of the two orexin receptors. When he got wind that Yanagisawa had engineered a mouse lacking orexins that slept in a manner characteristic of narcolepsy, the race was on.
Within weeks, Mignot and his team had submitted a paper to the journal Cell, revealing a defect in the gene encoding one of the orexin receptors. “This result identifies hypocretins [orexins] as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients,” they wrote. Kahlua—one of a litter of Dobermans all named after alcoholic beverages—lay sprawled across the cover of the issue. Yanagisawa and colleagues added their experimental evidence to the mix just two weeks later, also in Cell.
Under normal circumstances, a chemical messenger and its receptor work a lot like a key and lock. A key (the messenger) fits into a lock (its receptor) to open a door (cause a change within the target cell). In the case of Mignot’s Dobermans, a massive mutation had effectively jammed the lock of the orexin receptor, rendering the orexin useless.
Whether it’s the lock that doesn’t work, as in this case, or that the keys are missing, as they were in Yanagisawa’s mice, the upshot is the same. The door won’t open. The orexin system is broken. In human narcolepsy, there are many ways to break the orexin system. Occasionally, a brain tumor or head trauma is sufficient to do the damage. In most cases, however, narcolepsy is caused by the series of unfortunate events outlined above.
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