A new study by researchers at UC Santa Cruz shows how a genetic mutation delays the timing of the biological clock, causing a common sleep syndrome known as delayed sleep phase disorder.
People with this disease cannot 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 changing a key component of the biological clock that maintains the body’s daily rhythm. The new findings, published on October 26 in Procedure of the National Academy of Sciences, reveal the molecular mechanisms involved and point the way to possible treatments.
This mutation has a dramatic impact on people’s sleep patterns. 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 Partch, Corresponding Author, Professor of Chemistry and Biochemistry at UC Santa Cruz
Daily cycles in practically all aspects of our physiology are controlled by the cyclical interactions of clock proteins in our cells. Genetic variations that alter clock proteins can alter the timing of the clock and cause sleep phase disorders. A shortened clock cycle leads to people falling asleep and waking up earlier than normal (effect “morning lark”), while a longer clock cycle leads to people staying up late and sleeping (effect “night owl”).
Most of the mutations known to alter the clock are very rare, Partch said. They are important for scientists to understand how the clock works, but a given mutation can only affect one in a million people. However, the genetic variant identified in the 2017 study was found in about 1 in 75 people of European origin.
How often this particular mutation is implicated in delayed sleep phase disorder remains unclear, Partch said. Sleep patterns are complex – people stay up late for a variety of reasons – and disorders can be difficult to diagnose. The discovery of a relatively common genetic variation associated with a sleep phase disorder was therefore a remarkable development.
“This genetic marker is really common,” said Partch. “We still have a lot to understand about the role of prolonged timing in delaying the onset of sleep, but that one mutation is clearly an important cause of nighttime behavior in humans.”
The mutation affects a protein called cryptochrome, one of four major 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 together then suppress the activity of the first pair, turn themselves off and start the cycle again. This feedback loop is the central mechanism of the biological clock and drives 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 be omitted, and Partch’s lab found that this changes the tight binding of cryptochrome to the CLOCK: BMAL1 complex.
“The region that is cut out actually controls the activity of cryptochrome in a way that results in a 24-hour clock,” Partch explained. “Without it, cryptochrome binds tighter and stretches the length of the clock every day.”
The binding of these protein complexes involves a pocket in which the missing tail segment normally competes and disrupts the binding of the rest of the complex.
“How closely the complex partners are tied to this bag depends on how fast the clock runs,” explained Partch. “This tells us that we should look for drugs that bind to this pouch and serve the same purpose as the cryptochrome tail.”
Partch’s lab is currently doing just that, running screening assays to identify molecules that bind to the pocket in the watch’s molecular complex. “We now know that we need to target this bag in order to develop therapeutics that can shorten the time for people with delayed sleep phase disorder,” she said.
Partch has been studying the molecular structures and interactions of clock proteins for years. In a study published earlier this year, her lab showed how certain mutations can shorten the timing of the clock by affecting a molecular switching mechanism and turning some people into extreme morning larks.
She said the new study was inspired by 2017 work on the cryptochrome mutation from the laboratory of Nobel Prize winner Michael Young at Rockefeller University. The paper had just appeared when first author Gian Carlo Parico entered Partch’s laboratory as a PhD student, and he was determined to discover the molecular mechanisms responsible for the effects of the mutation.
The co-authors of the new paper include Parico and Partch Ivette Perez, Jennifer Friborgh and Britney Hernandez, all members of the Partch laboratory at UCSC, and Hsiau-Wei Lee, manager of the UCSC NMR facility. This research was funded by the National Institutes of Health and an HHMI Gilliam Fellowship for Parico.
University of California, Santa Cruz
Parico, GCG, et al. (2020) The human CRY1 tail controls circadian timing by regulating its association with CLOCK: BMAL1. PNAS. doi.org/10.1073/pnas.1920653117.
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