Posted by Maxime on August 11, 2006, at 13:14:06
New Sleep Gene Findings a Wake-Up Call
Caroline Cassels
July 13, 2006 — The first gene known to control the internal clock of humans and other mammals works exactly in reverse of what was previously believed, a new study suggests.
According to researchers at the University of Utah's Huntsman Cancer Institute, Salt Lake City, and the University of Michigan, Ann Arbor, the finding could mean a dramatic reversal in the way circadian rhythm disorders such as depression, insomnia, and chronic fatigue are treated.
The study is published in the July 11 issue of the Proceedings of the National Academy of Science.
Previously, it was believed the tau mutation caused a decrease in activity of the casein kinase 1 epsilon (CK1) gene, which in turn caused the body's circadian rhythm to speed up. But, in fact, researchers have now discovered the opposite is true, and it is an increase in activity of the CK1 gene that causes affected animals to have a shorter day.
According to principal investigator David Virshup, MD, from the University of Utah, several pharmaceutical companies have been developing inhibitors of CK1 activity based on the hypothesis that CK1 loss of function speeds up the clock.
"This new insight means drug studies are going to have to be redesigned. Our data suggest CK1 inhibitors may have effects on human circadian rhythms that are exactly the reverse of those predicted by previous models," Dr. Virshup told Medscape.
Fly in the Ointment
The research that led to this discovery began with a mathematical model of circadian rhythm developed by Daniel Forger, PhD, assistant professor of mathematics at the University of Michigan.
"This model, which is probably the best model we have of circadian rhythm, turned out to be highly predictive," said Dr. Virshup.
However, he added, there was one fly in the ointment. When Dr. Forger ran computer simulations of how the tau mutation influenced the mammalian body clock using the prevailing theory that the mutation decreased CK1 gene activity, the simulation showed the day became longer instead of shorter, causing the medical community to dismiss his model, said Dr. Virshup.
But when Dr. Forger ran a simulation based on the controversial idea that the tau mutation increased activity of the CK1 gene, the day shortened, just as it does in hamsters with the tau mutation.
Putting Theory Into Practice
In the meantime, Dr. Virshup and his group had made some similar observations that suggested the tau mutation increased rather than decreased activity of the CK1 gene.
On the strength of these observations and results from Dr. Forger's model, Dr. Virshup and his group used a drug that inhibited CK1 in cultured rat cells to determine its effect. According to published data, this should have caused the cells to have a shorter day. But instead, the experiment yielded the opposite result.
Dr. Virshup and his group had previously developed a method of measuring how quickly the circadian regulators PER 1 and PER 2 degraded. It is the disappearance of PER and a related protein from cells that resets the body's clock to start a new day.
According to Dr. Forger's model, the circadian rhythm within the cells would speed up because the tau gene mutation would degrade more quickly, and in fact, this is what happened in the new experiments. Because the mutant CK1 gene was more active, it causes PER to disappear more rapidly.
Potential ImpactDr. Virshup said this study is important for two reasons. First, it highlights the importance of developing detailed quantitative models and putting them to the test. "This mathematical model turned out to be an extremely powerful tool and was the first to suggest the conventional wisdom that the tau mutation causes a loss of function was incorrect," he said.
Second, CK1 is one of the best drug targets in the circadian rhythm system, and this finding could have major implications for patients suffering from familial advanced sleep phase syndrome, as well as more common circadian rhythm disorders such as seasonal affective disorder and depression.
The next step in this research will be to develop a mutant mouse model to determine whether, based on these findings, circadian rhythm can be regulated. Results are expected within a year, said Dr. Virshup.
Proc Natl Acad Sci. 2006;103:10618-10623
poster:Maxime
thread:675659
URL: http://www.dr-bob.org/babble/20060810/msgs/675659.html