Mechanism Involved in Adjusting Circadian Rhythm Identified

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.

This shows a man trying to sleep.

Researchers report the body’s clock is reset when a phosphate combines with a key protein in the brain. Image adapted from the McGill press release.

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.”

About this neuroscience research

Funding: Funding for this study was provided by the Canadian Institutes of Health Research, the U.S. National Institutes of Health, the Howard Hughes Medical Institute, the Fonds de recherche du Québec-Santé and a Banting Postdoctoral Fellowship.

Source: Chris Chipello – McGill University
Image Source: The image is adapted from the McGill press release
Original Research: Abstract for “Light-regulated translational control of circadian behavior by eIF4E phosphorylation” by Ruifeng Cao, Christos G Gkogkas, Nuria de Zavalia, Ian D Blum, Akiko Yanagiya, Yoshinori Tsukumo, Haiyan Xu, Choogon Lee, Kai-Florian Storch, Andrew C Liu, Shimon Amir & Nahum Sonenberg in Nature Neuroscience. Published online April 27 2015 doi:10.1038/nn.4010


Abstract

Light-regulated translational control of circadian behavior by eIF4E phosphorylation

The circadian (~24 h) clock is continuously entrained (reset) by ambient light so that endogenous rhythms are synchronized with daily changes in the environment. Light-induced gene expression is thought to be the molecular mechanism underlying clock entrainment. mRNA translation is a key step of gene expression, but the manner in which clock entrainment is controlled at the level of mRNA translation is not well understood. We found that a light- and circadian clock–regulated MAPK/MNK pathway led to phosphorylation of the cap-binding protein eIF4E in the mouse suprachiasmatic nucleus of the hypothalamus, the locus of the master circadian clock in mammals. Phosphorylation of eIF4E specifically promoted translation of Period 1 (Per1) and Period 2 (Per2) mRNAs and increased the abundance of basal and inducible PER proteins, which facilitated circadian clock resetting and precise timekeeping. Together, these results highlight a critical role for light-regulated translational control in the physiology of the circadian clock.

“Light-regulated translational control of circadian behavior by eIF4E phosphorylation” by Ruifeng Cao, Christos G Gkogkas, Nuria de Zavalia, Ian D Blum, Akiko Yanagiya, Yoshinori Tsukumo, Haiyan Xu, Choogon Lee, Kai-Florian Storch, Andrew C Liu, Shimon Amir & Nahum Sonenberg in Nature Neuroscience. Published online April 27 2015 doi:10.1038/nn.4010

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