Study Reveals Link Between Protein, Sleep Cycle

Could a recent study have discovered the key to manipulating circadian rhythms?

An international team of scientists, led by researchers at McGill and Concordia Universities in Montreal, discovered what could become a way for humans to re-set their ‘biological clock’ without light. This could lead to breakthroughs in treating a wide range of issues, from sleeping disorders to jetlag.

“Virtually all living beings on this planet show about 24 hour rhythmicity in their life activities,” Ruifeng Cao, a post-doctoral fellow at McGill and lead author of the study, said. “This rhythm is driven by the so-called ‘circadian clock’ in our body. In mammals including humans, the master clock is located in part of our brain called the hypothalamus. As the environmental cycles are constantly changing, the clock has to be continually adjusted to keep its accuracy. Light is the most important hand that touches and resets our body clock.”

The clock resets when phosphates combine with period proteins in the brain. This phosphorylation is triggered by light. The study focused on a protein called Eukaryotic Initiation Factor 4E (EIF4E).

“The two key proteins that are key for clock resetting are both called period proteins; period one and period two,” study co-author and professor in Concordia’s Department of Psychology Shimon Amir said. “We wanted to study how this process is being controlled. We focused on a protein called Eukaryotic Initiation Factor 4E. What that protein does is it takes RNA and brings it to a translation complex. What we wanted to know is how this protein is being controlled.”

Scientists mutated EIF4E in the brains of mice, preventing it from being phosphorylated. This led to the mice failing to respond to light pulses that result in clock resetting and failure to adapt to different cycles of light and darkness, according to Amir.

“We discovered that light activates a molecular pathway in the cell that leads to phosphorylation of EIF4E,” Amir said. “As a result, the RNA for period genes is converted into proteins. We knew that light induces the expression of RNA, that’s been studied before, but there was nothing known about whether light controls the second step, which is the conversion of RNA to protein.”

Previous studies have linked disruptions to the circadian clock with a variety of health risks. Some things that can cause disruptions have become part of people’s everyday routines.

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“In the modern society, trans-time zone travel, graveyard shifts, extensive use of night lights and night owl life styles all become health hazards that frequently disrupt our circadian rhythms,” Cao said. “Accumulating evidence demonstrates that disruption of circadian clock function is linked to a number of diseases such as cancer, diabetes and cardiovascular diseases. Thus, to treat the circadian abnormalities, we have to study the fundamental biological mechanisms that control our internal clocks.”

Amir said the results of the study show that the clock can be reset without a need for light by manipulating EIF4E. This could lead to new pharmaceutical products that could help people have some control over their circadian rhythms.

“Usually light is the most important factor for clock resetting,” Amir said. “Now that we have discovered the process by which RNA is converted to protein, perhaps we can develop a pharmacological agent that would act downstream from light. Maybe we could have a drug that would enhance phosphorylation of EIF4E which could control clock resetting.”

However, Amir also cautioned that EIF4E is responsible for more than just regulating circadian rhythms. He said scientists need to find a way to manipulate the protein as it relates to the circadian clock without altering its functions in other systems.

“This protein EIF4E is not there just to control clock proteins, it is a general translation mechanism that is involved in a lot of protein synthesis all over the body,” Amir said. “We would like to have selectivity and specificity of a drug so it would act on the clock itself and not act on any other processes.”

Cao said the next step for researchers could be studying the impact EIF4E has on these other areas of the body.

“The next interesting question would be ‘what is the importance of EIF4E phosphorylation in peripheral clocks?’ It is now known that virtually every cell in every tissue of our body has a clock,” Cao said. Normally the peripheral clocks are orchestrated by the master pacemaker, which is located in the suprachiasmatic nucleus in our brain. Since we have discovered EIF4E phosphorylation is a key regulator of the suprachiasmatic nucleus in the current study, it would be rational to expect that it may play a similarly important role in the peripheral clocks.”