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Body and mind

Circadian rhythm regulates protein activity in the brain

New research shows that sleep deprivation interferes with the rhythm of protein activity in the brain. In the long term, the discovery may influence understanding of how nervous system diseases develop.

New international research shows that people’s circadian rhythm and quality of sleep determine which proteins are active and inactive in the brain at different times of the day.

The research also shows that a poor night’s sleep severely disturbs the rhythm of protein activity. As most people know, this may adversely affect memory and ability to concentrate but may also have more far-reaching effects if the situation persists over time.

The discovery improves understanding of brain ageing and why sleeping well is so important to reduce the risk of developing nervous system diseases such as Alzheimer’s and Parkinson’s.

“Sleep regulates how well the brain works, but so far we have not sufficiently understood the biochemical context. We have now found evidence that the circadian rhythm regulates the activity of several thousand proteins in the brain biochemically,” explains Matthias Mann, Professor and Research Director, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen and Director, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.

The research has been published in Science.

Sleep regulates many functions including liver and brain

The circadian rhythm and sleep patterns are essential regulators of activity for humans and other animals.

Research by Maiken Nedergaard, a doctor and researcher at the University of Copenhagen, has shown that sleep helps to remove waste substances from the brain, and failure to remove them can damage the brain.

Sleep also regulates the functioning of most organs, the heart rhythm and body temperature, all of which are influenced by the Sun’s orbit across the sky and our activities during the day.

“Our research has shown that the circadian rhythm is closely linked to the activity of proteins in the liver,” explains Matthias Mann.

Phosphorylation activates proteins

The new study focused on the phosphorylation of proteins.

Proteins can be either active or inactive, and proteins are often activated by attaching a phosphate group (PO4) that turns on the protein so that it can perform its function.

The activity of various proteins increases and decreases during the day, and the new study shows that the circadian rhythm regulates the phosphorylation of the proteins in the brain so that they are active at specific times and not all the time.

For the body as a whole, it makes good sense for proteins not to be continuously active. For example, the proteins involved in metabolism do not need to be active when we sleep, but they should be when the day begins and we wash down breakfast with a cup of coffee.

This also applies to the brain, and the study shows that wake-to-sleep and sleep-to-wake transitions activate numerous brain proteins.

“We are the first researchers to use a new and advanced form of mass spectroscopy to link sleep patterns and the phosphorylation of proteins in and around brain synapses. Researchers previously performed RNA sequencing on the transcriptome to find the molecular biological context, but this is like looking for a lost key in the wrong place,” says Matthias Mann.

Sleep regulates the activity of 2000 proteins

The researchers investigated how sleep affects the phosphorylation of proteins in the synapses of mice by investigating the phosphorylation in their brains at different times of the day.

The mice were killed so that the researchers could analyse the concentrations of active and inactive proteins in their brain synapses.

The researchers found that the activity of the proteins was clearly correlated with the time of day when the mice were examined.

The link is cyclical, and the circadian rhythm regulates the activity of more than 8000 sites responsible for or associated with phosphorylation on 2000 proteins.

Sleep deprivation interferes with cyclical phosphorylation

In another experiment, the researchers interfered with the rest-activity cycles of the mice by waking the mice every few hours to determine how this affected the phosphorylation of the proteins in the brain.

The researchers examined the phosphorylation of the proteins in the synapses and found that the rhythmic variation usually present among 8000 phosphorylation sites, had almost completely disappeared. The activity of only about 100 phosphorylation sites continued to follow a cyclical rhythm whereas 98% of the phosphorylation sites did not.

“The phosphorylation of the proteins changed very drastically, and this must affect the function of the brain. The synapses are important for memory and learning, so these functions suffer most when the circadian rhythm is interfered with,” says Matthias Mann.

Matthias Mann emphasizes that the experiments have only been performed on mice, but he suspects that the same pattern will apply to humans.

Medicine can regulate phosphorylation

Matthias Mann speculates whether dysregulated phosphorylation of proteins in the brain may be a mechanism causing brain ageing and the development of diseases such as Alzheimer’s and Parkinson’s.

This presents some interesting pharmaceutical opportunities if there is a link.

Kinases carry out most of the phosphorylation, and they can be inhibited by using medicine, such as in certain types of cancer treatments.

Phosphorylation may be manipulated in the future to restore a better circadian rhythm among people with sleep deprivation, which can help to counteract many of its negative side-effects.

Initially, researchers can also start by examining the phosphorylation of mice with, for example, Alzheimer’s to determine whether there is a possible association.

“I guess that we will find dysregulated phosphorylation of proteins in the synapses in some of these diseases. This opens up some interesting opportunities for pharmaceutical intervention,” says Matthias Mann.

Sleep-wake cycles drive daily dynamics of synaptic phosphorylation” has been published in Science. Matthias Mann is a Professor at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Matthias Mann
Research director, professor
The Mann group - Clinical Proteomics will undertake an ambitious new biomedical research programme involving proteomics of blood/plasma for patient phenotyping. The aim is to identify biological markers for diabetes, obesity and other metabolic disorders that can be used to improve diagnosis and develop more individualized therapies. The group will build on its world leading expertise in proteomics technologies and implement a high sensitivity and high accuracy platform to analyze the proteomics of up to 100 individuals per day at great accuracy and depth of coverage. Together with partners at Steno Diabetes Center, Rigshospitalet, Panum Institute, the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen and elsewhere, they will apply this platform to characterize the blood proteome and how it is associated with known and novel metabolic risk factors for diabetes and cardiovascular disease.