A new study by researchers at UC Santa Cruz shows how a genetic mutation throws off the biological clock time, causing a common sleep syndrome called delayed sleep disorder.
People with this condition can not sleep late at night (often after 2 am) and have difficulty getting up in the morning. In 2017, scientists discovered a surprisingly common mutation that causes this sleep disorder by changing a key component of the biological clock that maintains the body’s daily rhythms. The new findings, released on October 26 at Proceedings of the National Academy of Sciences, discover the molecular mechanisms involved and point the way to potential treatments.
“This mutation has dramatic effects on human sleep, so it is exciting to identify a specific mechanism in the biological clock that links the biochemistry of this protein to the control of human sleep behavior.”
Carrie Parch, Corresponding Author, Professor of Chemistry and Biochemistry at UC Santa Cruz
Daily cycles in virtually every aspect of our physiology are driven by cyclic interactions of clock proteins in our cells. Genetic variations that alter clock proteins can alter clock time and cause sleep disturbances. The shortened clock cycle causes people to fall asleep and wake up earlier than normal (the “morning ariga” effect), while the longer clock cycle causes people to stay up late and sleep (the “night owl effect”).
“Most mutations that are known to change the clock are very rare,” Parch said. They are important to scientists as clues to understanding the mechanisms of the clock, but a given mutation can only affect one in a million people. The genetic variant identified in the 2017 study, however, was found in about one in 75 people of European descent.
How often this particular mutation is involved in a delayed sleep disorder remains unclear, Parch said. Sleeping behavior is complex; people stay up late for many different reasons; and disorders can be difficult to diagnose. So, the discovery of a relatively common genetic variation associated with the sleep phase disorder was an amazing development.
“This genetic marker is really widespread,” Parch said. “We still have a lot to understand about the role of extended clock timing in delayed sleep onset, but this one mutation is obviously an important cause of late-night behavior in humans.
The mutation affects a protein called cryptochrome, one of the four major proteins in the clock. Two of the clock proteins (CLOCK and BMAL1) form a complex that includes genes for the other two (period and cryptochrome), which then combine to suppress the activity of the first pair, thus shutting down and starting the cycle again. This feedback loop is the central mechanism of the biological clock, moving daily fluctuations in genetic activity and protein levels throughout the body.
The cryptochrome mutation causes a small segment of the “tail” of the protein to stay out, and Parch’s lab found that this changes how tightly the cryptochrome binds to the CLOCK: BMAL1 complex.
“The region to be extracted actually controls the activity of cryptochrome in a way that leads to a 24-hour clock,” Parch explained. “Without it, the cryptochrome binds more tightly and stretches around the clock every day.
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 complex partners are tied to this pocket determines how fast the watch works,” Parch explained. “This tells us that we need to look for drugs that bind to that pocket and can serve the same purpose as the cryptochrome tail.”
Parch Laboratory is currently doing just that, conducting screening tests to identify molecules that bind to the pocket in the molecular complex of the watch. “We now know that we need to streamline that pocket to develop therapies that can shorten the clock for people with delayed sleep disorders,” she said.
Parch has been studying the molecular structures and protein interactions of the clock for years. In a study published earlier this year, her lab showed how certain mutations can shorten clock time by affecting the molecular switch mechanism, making some people extreme morning sharks.
She said the new study was inspired by a 2017 paper on a cryptochrome mutation from the laboratory of Nobel laureate Michael Young at Rockefeller University. The paper had just been published when the first author, ianan Carlo Parico, joined Parch’s laboratory as a graduate student, and he was determined to discover the molecular mechanisms responsible for the effects of mutation.
In addition to Parico and Parch, co-authors of the new paper include Yvette Perez, Ennifer Friborg and Britney Hernandez, all members of Parch’s laboratory at UCSC, and Xiau-Wei Lee, manager of the USCM MRI Facility. This research was funded by the National Institutes of Health and HHMI Gilliam Scholarship for Parico.
University of California, Santa Cruz
Pariko, GCG, etc. (2020) The human tail CRY1 controls the circadian timing by regulating its connection to the HOUR: BMAL1. PNAS. doi.org/10.1073/pnas.1920653117.