July 12, 2006 Proteins that regulate sleep and biological timing in the body work much differently than previously thought, meaning drug makers must change their approach to making drugs for sleep disorders and depression and other timing-related illnesses.
The surprise finding is an about-face from previous research, said Daniel Forger, assistant professor of math at the University of Michigan. Forger and his collaborators from the University of Utah's Huntsman Cancer Institute have written a paper on the topic, which will appear on in the July 11 issue of the Proceedings of the National Academy of Science. It will appear the week of July 3 on line, at http://www.pnas.org/cgi/doi/10.1073/pnas.0604511103.
Scientists studied two proteins (one called CKIe and another called PERIOD) that help regulate timing in the body, and looked at how those proteins function in cells, said Forger. One of the proteins causes the other protein to degrade, and the body knows what time it is by how much or how little PERIOD protein is present at any one time in the body. The body's clock is called a circadian rhythm.
Drug makers spend billions to develop drugs to help people with sleep disorders, and other disorders impacted by our biological clocks. Drugs to restore a healthy circadian rhythm by manipulating the levels of PERIOD proteins are currently under development.
One such sleep disorder is called Familial Advanced Sleep Phase Syndrome and this is caused by a gene mutation, Forger said. Patients suffering from the disease routinely wake very early, say at 4 a.m. and must go to bed early, at say 7 p.m. said Forger.
If put in a cave with no light, these people should have a shortened day, Forger said. This means that on our time, they would wake the first day at say, 6 a.m. then at 4 a.m. then at 2 a.m. on subsequent days.
"When they have light and dark cycles in the normal world, they pretty much have to live in a 24-hour day," Forger said. "They were able to adjust but the price they have to pay is their body wakes up early, and they have to go to bed earlier than we do."
"The theory was that the mutation caused (more of the PERIOD protein) so you get a short day so you want to get up very early in the morning," Forger said. But, during testing they found the opposite is true: the mutation actually caused the PERIOD to degrade more quickly so that less is present in the body.
The finding wasn't a complete surprise to Forger, who develops math models of the circadian rhythms. Forger's computer models always said that the opposite of the prevailing thinking should be true—that the PERIOD protein should degrade more quickly when the mutation is present.
"I had this prediction for a year or two," Forger said. "Basically, people said this is ridiculous, you're a mathematician, what do you know…"
Then he met David Virshup, M.D., while giving an invited talk at the University of Utah. Virshup's previous research was on the gene involved in circadian rhythms and its role in cancer development. Their experiments had also suggested that genetic mutation caused the protein to degrade more quickly. Virshup suggested they test Forger's simulation.
The researchers took cell cultures and observed that for those with the mutated gene, the protein only took a couple hours to degrade. For the normal gene, it took 8-10 hours.
Next, Virshup said, his team will begin testing ways to regulate the circadian rhythm in mice, a necessary step before new drugs can be developed.
Funding for the study was provided by the National Institutes of health, the Huntsman Cancer Institute and the Sloan Foundation.
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