Scientists discover how a common mutation leads to 'night owl' sleep disorder
October 27, 2020
Science Daily/University of California - Santa Cruz
A new study by researchers at UC Santa Cruz shows how a genetic mutation throws off the timing of the biological clock, causing a common sleep syndrome called delayed sleep phase disorder.
People with this condition are unable to fall asleep until late at night (often after 2 a.m.) and have difficulty getting up in the morning. In 2017, scientists discovered a surprisingly common mutation that causes this sleep disorder by altering a key component of the biological clock that maintains the body's daily rhythms. The new findings, published October 26 in Proceedings of the National Academy of Sciences, reveal the molecular mechanisms involved and point the way toward potential treatments.
"This mutation has dramatic effects on people's sleep patterns, so it's exciting to identify a concrete mechanism in the biological clock that links the biochemistry of this protein to the control of human sleep behavior," said corresponding author Carrie Partch, professor of chemistry and biochemistry at UC Santa Cruz.
Daily cycles in virtually every aspect of our physiology are driven by cyclical interactions of clock proteins in our cells. Genetic variations that change the clock proteins can alter the timing of the clock and cause sleep phase disorders. A shortened clock cycle causes people to go to sleep and wake up earlier than normal (the "morning lark" effect), while a longer clock cycle makes people stay up late and sleep in (the "night owl" effect).
Most of the mutations known to alter the clock are very rare, Partch said. They are important to scientists as clues to understanding the mechanisms of the clock, but a given mutation may only affect one in a million people. The genetic variant identified in the 2017 study, however, was found in around one in 75 people of European descent.
How often this particular mutation is involved in delayed sleep phase disorder remains unclear, Partch said. Sleep behavior is complex -- people stay up late for many different reasons -- and disorders can be hard to diagnose. So the discovery of a relatively common genetic variation associated with a sleep phase disorder was a striking development.
"This genetic marker is really widespread," Partch said. "We still have a lot to understand about the role of lengthened clock timing in delayed sleep onset, but this one mutation is clearly an important cause of late night behavior in humans."
The mutation affects a protein called cryptochrome, one of four main clock proteins. Two of the clock proteins (CLOCK and BMAL1) form a complex that turns on the genes for the other two (period and cryptochrome), which then combine to repress the activity of the first pair, thus turning themselves off and starting the cycle again. This feedback loop is the central mechanism of the biological clock, driving daily fluctuations in gene activity and protein levels throughout the body.
The cryptochrome mutation causes a small segment on the "tail" of the protein to get left out, and Partch's lab found that this changes how tightly cryptochrome binds to the CLOCK:BMAL1 complex.
"The region that gets snipped out actually controls the activity of cryptochrome in a way that leads to a 24-hour clock," Partch explained. "Without it, cryptochrome binds more tightly and stretches out the length of the clock each day."
The binding of these protein complexes involves a pocket where the missing tail segment normally competes and interferes with the binding of the rest of the complex.
"How tightly the complex partners bind to this pocket determines how quickly the clock runs," Partch explained. "This tells us we should be looking for drugs that bind to that pocket and can serve the same purpose as the cryptochrome tail."
Partch's lab is currently doing just that, conducting screening assays to identify molecules that bind to the pocket in the clock's molecular complex. "We know now that we need to target that pocket to develop therapeutics that could shorten the clock for people with delayed sleep phase disorder," she said.
Partch has been studying the molecular structures and interactions of the clock proteins for years. In a study published earlier this year, her lab showed how certain mutations can shorten clock timing by affecting a molecular switch mechanism, making some people extreme morning larks.
She said the new study was inspired by the 2017 paper on the cryptochrome mutation from the lab of Nobel Laureate Michael Young at Rockefeller University. The paper had just come out when first author Gian Carlo Parico joined Partch's lab as a graduate student, and he was determined to discover the molecular mechanisms responsible for the mutation's effects.
https://www.sciencedaily.com/releases/2020/10/201027105354.htm
Daylight Saving Time has long-term effects on health
November 4, 2019
Science Daily/Vanderbilt University Medical Center
The annual transition to and from daylight saving time (DST) has clinical implications that last longer than the days where clocks "fall back" or "spring forward."
Over time, DST eliminates bright morning light that critically synchronizes biologic clocks, which can be associated with increased risk of heart attack and ischemic stroke, as well as other negative effects of partial sleep deprivation.
Average sleep duration shrinks by 15 to 20 minutes for adults during DST transitions, which may also increase the risk of fatal accidents.
"People think the one-hour transition is no big deal, that they can get over this in a day, but what they don't realize is their biological clock is out of sync," said Beth Ann Malow, MD, Burry Chair in Cognitive Childhood Development, and professor of Neurology and Pediatrics in the Sleep Disorders Division at Vanderbilt University Medical Center.
"It's not one hour twice a year. It's a misalignment of our biologic clocks for eight months of the year. When we talk about DST and the relationship to light, we are talking about profound impacts on the biological clock, which is a structure rooted in the brain. It impacts brain functions such as energy levels and alertness," she said.
Malow and colleagues published a JAMA Neurology commentary today recapping large epidemiological studies that advocate for ending the practice of setting clocks forward or back.
Some people may have more flexible circadian rhythms and adjust quickly while others are more sensitive. Malow, an expert on autism and sleep, said that the transition impacts some children with autism for weeks or months.
While the sleep and circadian communities believe returning to standard time may be more biologically appropriate, gaining political buy-in for a nationwide change remains a challenge. State legislation is "all over the map," with some states considering a return to standard time and others in favor of permanent DST. Tennessee has passed legislation supporting permanent DST, although such a change would require action from the U.S. Congress
https://www.sciencedaily.com/releases/2019/11/191104144133.htm
Biological clock influences immune response efficiency
September 24, 2019
Science Daily/McGill University
The biological clock influences immune response efficacy. Indeed, CD8 T cells, which are essential to fight infections and cancers, function very differently according to the time of day.
According to a recent study published in Proceedings of the National Academy of Sciences, the biological clock influences immune response efficacy. Indeed, CD8 T cells, which are essential to fight infections and cancers, function very differently according to the time of day. The study was carried out by a team of researchers led by Nicolas Cermakian, PhD, of the Douglas Research Centre, and Nathalie Labrecque, PhD, of the Maisonneuve-Rosemont Hospital Research Centre.
We know that circadian rhythms are generated by "clock genes," which influence most organs and cells -- including those of the immune system, whose function varies according to the time of day. Accordingly, circadian rhythms are found for various aspects of physiology, including sleep, nutrition, hormonal activity, and body temperature. These daily rhythms help the body adapt to cyclical changes in the environment, such as seasons and the day and night cycle.
In earlier research, the team had demonstrated that T cells react more or less strongly to a foreign body according to the time of day, but the role of the biological clock in this phenomenon remained unknown. "Using a mouse vaccine model, we observed that after vaccination, the strength of the CD8 T cell response varied according to the time of day. Conversely, in mice whose CD8 T cells were deficient for the clock gene, this circadian rhythm was abolished, and response to the vaccine was diminished in the daytime," explains Dr. Cermakian, who is also Professor at the McGill University Department of Psychiatry.
"Our study shows that T cells are more prone to be activated at certain times of the day. Identifying the mechanisms through which the biological clock modulates the T cell response will help us better understand the processes that regulate optimal T cell responses. This knowledge will contribute to improving vaccination strategies and cancer immune therapies," states Nathalie Labrecque, Professor at the Departments of Medicine and Microbiology, Infectious Diseases and Immunology at Université de Montréal.
https://www.sciencedaily.com/releases/2019/09/190924125015.htm
Another Reason to Avoid High-Fat Diet: It Can Disrupt Our Biological Clock
December 31, 2008
Science Daily/Hebrew University of Jerusalem
Indulgence in a high-fat diet can not only lead to overweight because of excessive calorie intake, but also can affect the balance of circadian rhythms – everyone’s 24-hour biological clock, Hebrew University of Jerusalem researchers have shown.
The biological clock regulates the expression and/or activity of enzymes and hormones involved in metabolism, and disturbance of the clock can lead to such phenomena as hormone imbalance, obesity, psychological and sleep disorders and cancer.
While light is the strongest factor affecting the circadian clock, Dr. Oren Froy and his colleagues of the Institute of Biochemistry, Food Science and Nutrition at the Hebrew University’s Robert H. Smith Faculty of Agriculture, Food and Environment in Rehovot, have demonstrated in their experiments with laboratory mice that there is a cause-and-effect relation between diet and biological clock imbalance.
To examine this thesis, Froy and his colleagues, Ph.D. student Maayan Barnea and Zecharia Madar, the Karl Bach Professor of Agricultural Biochemistry, tested whether the clock controls the adiponectin signaling pathway in the liver and, if so, how fasting and a high-fat diet affect this control. Adiponectin is secreted from differentiated adipocytes (fat tissue) and is involved in glucose and lipid metabolism. It increases fatty acid oxidation and promotes insulin sensitivity, two highly important factors in maintaining proper metabolism.
The researchers fed mice either a low-fat or a high-fat diet, followed by a fasting day, then measured components of the adiponectin metabolic pathway at various levels of activity. In mice on the low-fat diet, the adiponectin signaling pathway components exhibited normal circadian rhythmicity. Fasting resulted in a phase advance. The high-fat diet resulted in a phase delay. Fasting raised and the high-fat diet reduced adenosine monophosphate-activated protein kinase (AMPK) levels. This protein is involved in fatty acid metabolism, which could be disrupted by the lower levels.
In an article soon to be published by the journal Endocrinology, the researchers suggest that this high-fat diet could contribute to obesity, not only through its high caloric content, but also by disrupting the phases and daily rhythm of clock genes. They contend also that high fat-induced changes in the clock and the adiponectin signaling pathway may help explain the disruption of other clock-controlled systems associated with metabolic disorders, such as blood pressure levels and the sleep/wake cycle.
http://www.sciencedaily.com/releases/2008/12/081228191054.htm