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06/24/91

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NARCOLEPSY DISCOVERIES PROVIDE CLUES TO NORMAL SLEEP

STANFORD -- New clues to the genetic and neurophysiological basis of narcolepsy--the disease of sudden, uncontrollable attacks of sleep--may eventually lead researchers to a better understanding of both the disorder and of normal sleep.

Scientists at Stanford and the University of California, Los Angeles, recently reported the identification of a specific group of cells in the brain that are active during cataplexy--one of the primary and most dramatic symptoms of narcolepsy--which causes brief periods of loss of muscle control.

In addition, earlier this year a team of Stanford researchers led by Dr. Emmanuel Mignot, director of narcolepsy research at the Stanford Sleep Research Center, determined that the gene associated with narcolepsy in dogs is related to a human immune system gene.

Together these findings are important steps toward a better understanding of narcolepsy, which afflicts about 250,000 people in the United States. The genetic and neurophysiological studies of narcolepsy are complementary, the researchers said, because identifying the specific brain areas involved in the disease will help reveal how particular genes cause its unique symptoms.

Cataplexy is a sudden attack of paralysis caused by excitement such as laughter, anger or surprise. A person with narcolepsy might collapse to the ground when he or she hears a good joke. During cataplexy, the person is awake and aware of his or her surroundings, yet unable to move, usually for a few seconds to a minute.

Researchers have long suspected that cataplexy might be related to normal REM sleep, the sleep stage associated with dreaming. In REM sleep, outputs from the brain that normally command the body to move while awake are suppressed, preventing us from acting out our dreams. Scientists have theorized that if the paralysis of cataplexy and the paralysis of normal REM sleep are related, then the same brain cells should be active in both states.

In the May 31 issue of the journal Science, UCLA and Stanford researchers reported finding that a subset of the cells active during REM sleep were also active immediately prior to and during attacks of cataplexy.

The researchers are now searching for other components in the circuit of nerve cells in the brain responsible for cataplexy, said Dr. Jerome Siegel, professor of psychiatry at the UCLA School of Medicine and lead author of the report. They hope that understanding cataplexy will shed light on REM sleep, whose mechanisms and functions are poorly understood.

The neurophysiological studies performed at UCLA were conducted on narcoleptic dogs bred in Stanford's unique canine narcolepsy colony. The Stanford colony represents the only animal model of a sleep disorder in the world. Like human narcoleptics, narcoleptic dogs often lose control of their muscles when excited. The colony allows researchers to trace the transmission of the disease through a series of carefully planned breedings and to observe cataplexy in a laboratory, in a manner that would be impossible in humans.

By studying the patterns of the disease in large families of narcoleptic Labradors and Dobermans, the Stanford team determined that canine narcolepsy is transmitted by a single gene, which they named canarc-1. Their most recent finding, reported in the April 15 issue of the Proceedings of the National Academy of Sciences, supports previous evidence that narcolepsy is related to the immune system in some way. They found that canarc-1 is related to a human gene that regulates certain proteins that compose antibodies, the body's disease- fighting agents.

This finding represents the discovery of only the second gene whose function is related to sleep in some way. The first such gene, also an immune system gene, is called HLA-DR2. In 1983, Japanese researchers demonstrated that almost all human narcoleptics carry this gene.

But an understanding of the role the DR2 gene plays in human narcolepsy has remained elusive. Not all narcoleptics carry the DR2 gene and about 30 percent of the general population carries it, leading scientists to the conclusion that other genes and environmental factors must also be involved.

When they first found the canarc-1 gene, Mignot's team tested the hypothesis that it could be the canine equivalent of the human DR2 gene but found that the two were not related. However, their recent discovery strongly supports an immune system involvement in human narcolepsy and provides researchers with a tool to explore the relationship of sleep and the immune system at the molecular level.

Although sleep comprises a third of our lives, its function is still a mystery. "Identifying the cause of narcolepsy will not only help treat narcoleptic patients, but could also open a new avenue of exploration for investigating the control of normal sleep," said Mignot. -lbj-

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