An international team of scientists has
discovered what amounts to a molecular reset button for our internal
body clock. Their findings reveal a potential target to treat a range of
disorders, from sleep disturbances to other behavioral, cognitive, and
metabolic abnormalities, commonly associated with jet lag, shift work
and exposure to light at night, as well as with neuropsychiatric
conditions such as depression and autism.
In a study published online April 27 in Nature Neuroscience,
the authors, led by researchers at McGill and Concordia universities in
Montreal, report that the body's clock is reset when a phosphate
combines with a key protein in the brain. This process, known as
phosphorylation, is triggered by light. In effect, light stimulates the
synthesis of specific proteins called Period proteins that play a
pivotal role in clock resetting, thereby synchronizing the clock's
rhythm with daily environmental cycles.
Shedding light on circadian rhythms
"This study is the first to reveal a mechanism that explains how
light regulates protein synthesis in the brain, and how this affects the
function of the circadian clock," says senior author Nahum Sonenberg, a
professor in McGill's Department of Biochemistry.
In order to study the brain clock's mechanism, the researchers
mutated the protein known as eIF4E in the brain of a lab mouse so that
it could not be phosphorylated. Since all mammals have similar brain
clocks, experiments with the mice give an idea of what would happen if
the function of this protein were blocked in humans.
Running against the clock
The mice were housed in cages equipped with running wheels. By
recording and analyzing the animals' running activity, the scientists
were able to study the rhythms of the circadian clock in the mutant
mice.
The upshot: the clock of mutant mice responded less efficiently than
normal mice to the resetting effect of light. The mutants were unable to
synchronize their body clocks to a series of challenging light/dark
cycles -- for example, 10.5 hours of light followed by 10.5 hours of
dark, instead of the 12-hour cycles to which laboratory mice are usually
exposed.
"While we can't predict a timeline for these findings to be
translated into clinical use, our study opens a new window to manipulate
the functions of the circadian clock," says Ruifeng Cao, a postdoctoral
fellow in Dr. Sonenberg's research group and lead author of the study.
For co-author Shimon Amir, professor in Concordia's Department of
Psychology, the research could open a path to target the problem at its
very source. "Disruption of the circadian rhythm is sometimes
unavoidable but it can lead to serious consequences. This research is
really about the importance of the circadian rhythm to our general
well-being. We've taken an important step towards being able to reset
our internal clocks -- and improve the health of thousands as a result."
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