A new study by researchers 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 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.
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, the author 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, the author 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," the author 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 the 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," the author 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," the author 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."
The 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," the author said.
https://www.pnas.org/content/early/2020/10/23/1920653117
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fthe-cry1-tail-controls&filter=22
How a common mutation leads to sleep disorder
- 987 views
- Added
Edited
Latest News
Metabolic rewiring promotes…
By newseditor
Posted 18 Apr
A drug to prevent flu-induc…
By newseditor
Posted 18 Apr
New origin of deep brain waves
By newseditor
Posted 17 Apr
Starving cells hijack prote…
By newseditor
Posted 17 Apr
Miniature battery-free epid…
By newseditor
Posted 17 Apr
Other Top Stories
First scans show how the LSD drug affects the brain
Read more
Astrocytes and neuropathic pain!
Read more
A mutation in a mitochondrial protein leads to Abeta accumulation
Read more
How the brain consolidates memory during deep sleep
Read more
Mouse pups with human mutation show signs of stuttering
Read more
Protocols
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Modular dual-color BiAD sen…
By newseditor
Posted 31 Mar
Publications
How does the microbiota con…
By newseditor
Posted 18 Apr
The integrated stress respo…
By newseditor
Posted 18 Apr
The immunobiology of herpes…
By newseditor
Posted 17 Apr
Circulating microbiome DNA…
By newseditor
Posted 17 Apr
Spindle oscillations in com…
By newseditor
Posted 17 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar