"Sometimes we discover things in flies that have no direct relevance in higher order animals. In this case, because we found the protein in a location where it likely plays a role in circadian rhythms and sleep, we are encouraged that this protein may do the same thing in mice and people," says Mark Wu. (Credit: Anne Helmond/Flickr)

‘Wide awake’ gene sabotages sleep

Exhausted fruit flies have helped scientists find a mutant gene that disrupts how the biological clock sets the timing for sleep.

The new research also identifies a protein made by normal, non-mutated copies of the same gene, a protein that promotes sleep early in the night and properly regulates sleep cycles.

“We know that the timing of sleep is regulated by the body’s internal biological clock, but just how this occurs has been a mystery,” says study leader Mark N. Wu, assistant professor of neurology, medicine, genetic medicine, and neuroscience at the Johns Hopkins University School of Medicine.

“We have now found the first protein ever identified that translates timing information from the body’s circadian clock and uses it to regulate sleep.”

Genes and the proteins they produce are often the same in different species, so researchers suspect their work could lead to new treatments for people whose insomnia or abnormal work schedules keep them awake long after their heads hit the pillow.

That suspicion has been reinforced by preliminary studies in mice. A report on the fruit fly work appears online in the journal Neuron.

Time to shut down and sleep

Researchers studied thousands of fruit fly colonies, each with a different set of genetic mutations, and analyzed their sleep patterns. One group of flies, carrying a mutation in the gene the team would later call Wide Awake (or Wake for short), had trouble falling asleep at night, a malady that looked a lot like sleep-onset insomnia in humans.

The investigators say the normal, non-mutated Wake appears to be the messenger from the circadian clock to the brain, telling it that it’s time to shut down and sleep.

After isolating Wake, Wu’s team determined that, when working properly, it helps shut down arousal neurons of the brain by making them more responsive to signals from an inhibitory neurotransmitter called GABA. Wake does this in the early evening, promoting sleep at the right time.

Flies with a mutated Wake gene were not getting enough GABA signal to quiet their arousal circuits at night, keeping them agitated and awake.

Mammals’ master clock

The same gene was found in every animal the researchers studied: humans, mice, rabbits, chickens, even worms. When they looked to see where Wake was located in the mouse brain, they found that it was expressed in the suprachiasmatic nucleus, the master clock in mammals. The fact that the Wake protein was expressed in high concentrations there is significant, Wu says.

“Sometimes we discover things in flies that have no direct relevance in higher order animals. In this case, because we found the protein in a location where it likely plays a role in circadian rhythms and sleep, we are encouraged that this protein may do the same thing in mice and people.”

The hope is that someday, by manipulating Wake, possibly with a medication, researchers can help shift workers, military personnel, and sleep-onset insomniacs sleep better.

“This novel pathway may be a place where we can intervene,” Wu says.

This work was supported by grants from the National Institute of General Medical Sciences, the National Institute of Neurological Disorders and Stroke and a Burroughs Wellcome Fund Career Award for Medical Scientists.

Source: Johns Hopkins University

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