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Stanford Report, September 6, 2000

Lack of brain protein causes sleeping disorder narcolepsy in humans  


A year after finding the defect that causes narcolepsy in dogs, Stanford researchers have made the leap from canines to humans to show that people with the sleep disorder have a breakdown in the same molecular pathway. The finding sets the stage for a new form of treatment for the disabling condition.

"Narcolepsy is a very debilitating disease with massive social consequences," said Juliette Faraco, PhD, one of the primary authors of the new study, which appears in the September 1 issue of Nature Medicine. Now with a specific drug target to work on, Faraco said, researchers have new hope for developing a cure for narcolepsy.

The Stanford team, lead by Emmanuel Mignot, MD, PhD, associate professor of psychiatry and director of the Stanford Center for Narcolepsy, searched for defects in the brains and genes of narcolepsy patients from around the world. The team found that a small protein ­ or peptide ­ present in the brain cells of most people was absent in every brain of the people with narcolepsy that they studied.

"We think this is the cause of most human cases of narcolepsy ­ that patients don't have this peptide in the brain," said Mignot. "Now we need to develop a drug that can go into the brain to replace it."

The peptide, called hypocretin, was first identified as a culprit for narcolepsy when Mignot and his colleagues found that dogs with narcolepsy had a problem in one of the hypocretin genes. Hypocretin was being produced in the animals but there was a breakdown in the communication system that allowed hypocretin-generated messages to be transmitted into the cell.

Surprisingly, the researchers found that people with narcolepsy generally have intact hypocretin genes. But they found that there is a malfunction further along the hypocretin production line. The peptide is not being produced where it is needed ­ in the brain, where hypocretin seems to be responsible for promoting wakefulness.

The cells that make hypocretin were either completely missing in the brains of narcolepsy patients, or the few cells that remained were not making the peptide. According to Faraco, 10,000 to 15,000 of these cells can be found in normal brains and none in the brains of those with narcolepsy.

"We think something specifically kills the cells that make hypocretin," said Mignot. "We don't know how or why, but it's most likely an autoimmune disease."

Mignot likens the loss of hypocretin-producing neurons in narcolepsy patients to other disorders such as the loss of insulin-producing cells that leads to diabetes and the loss of dopamine-
producing neurons associated with Parkinson's disease.

Faraco is a postdoctoral fellow in the laboratory of Emmanuel Mignot. Christelle Peyron, PhD, is co-lead author of the study. Researchers from Leiden University Medical Center, Netherlands; H.U.G., Belle-idee, Division de Neuropsychiatrie, Geneva, Switzerland; Charles University, Prague, Czech Republic; University of Michigan and Geriatrics, Educational and Clinical Center VAMC, Ann Arbor, Mich.; Albert Einstein college of Medicine, New York; and Neurocrine Biosciences Inc., San Diego, Calif., also contributed to the study. Funding was provided by the National Institutes of Health. SR