Most of us have experienced the annoyances associated with jet lag or possibly some mild depression that follows the long dark winters in the northern parts of the globe. For many years scientists have understood that light exposure effects a group of nerve cells within the brain called the suprachiasmatic nucleus, which in turn sets the body’s circadian rhythm, allowing us to compensate for jet lag symptoms in a relatively short period of time. Yet, the underlying molecular mechanisms that cause these changes within various parts of the brain have eluded scientists.
However, an international team of researchers led by scientists at McGill and Concordia Universities believe they have uncovered a molecular reset pathway for the body’s master clock. The potential implications from these findings could assist in uncovering therapeutic targets for a range of disorders, from sleep disturbances to neuropsychiatric conditions such as depression and even autism.
“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, Ph.D., professor in the department of biochemistry at McGill University and senior author on the current study.
The findings from this study were published recently in Nature Neuroscience through an article entitled “Light-regulated translational control of circadian behavior by eIF4E phosphorylation.”
Dr. Sonenberg and his colleagues focused on a molecule known as eukaryotic translation initiation factor 4E (eIF4E), which has been known to play a major role in protein translation. For this study, the researcher created a mutant version of eIF4E that was incapable of being phosphorylated and inserted it into the brains of laboratory mice.
The researchers then observed the running wheel activity of mice after challenging them with a series of changes to their light exposure durations. Interestingly, they found that the eIF4E mutant mice were unable to synchronize their body clocks to the changes in light exposure.
“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, Ph.D., postdoctoral fellow in Dr. Sonenberg's research group and lead author of the current study.
Additionally, the investigators found that the phosphorylation of eIF4E specifically promoted the translation of two proteins previously known to play a role in maintaining normal circadian rhythm, Period 1 and Period 2. Specifically, the research team observed increased mRNA transcript levels for Period 1 and 2, as well as an increased abundance of the basal and inducible Period proteins—ultimately facilitating the reset of the circadian clock and allowing for precise timekeeping.
“Disruption of the circadian rhythm is sometimes unavoidable but it can lead to serious consequences,” explained Shimon Amir, Ph.D., professor of psychology at Concordia University and co-author on the current study. “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.”
