This could help not only people with Familial Advanced Sleep Phase Syndrome or FASP mutation, but also those whose sleep patterns are disrupted due to shift work, jet lag, and other contemporary lifestyle challenges.

Our body’s internal clocks, known as molecular clocks, play a crucial role in aligning our physiological functions with the natural rhythm of day and night. They regulate our sleep-wake cycles and coordinate various aspects of our body’s functions. Scientists who study these molecular mechanisms have made a significant discovery that sheds light on how our biological clocks are timed.

The latest research, published in Molecular Cell today, provides valuable insights into the molecular interactions that are disrupted in individuals with a hereditary sleep disorder known as Familial Advanced Sleep Phase Syndrome (FASP).

This syndrome arises from a genetic mutation that causes the clock to operate on a 20-hour cycle instead of the usual 24-hour cycle, resulting in affected individuals being extreme “morning larks.”

“It’s like having permanent jet lag, because their internal clock never gets caught up with the daylength,” comments corresponding author Carrie Partch. “The FASP mutation was discovered 20 years ago, and we knew it had a huge effect, but we didn’t know how or why.”

The genetic alteration, known as the FASP mutation, impacts a crucial component of our body’s biological clock, namely the Period protein, by modifying a single unit of its structure. Recent research uncovers how this subtle alteration creates a ripple effect, disrupting the Period protein’s ability to communicate with an enzyme known as casein kinase 1. This disruption leads to a reduction in the Period protein’s stability and accelerates a key phase in the biological clock’s rhythm.

First author Jonathan Philpott, a post-doctoral scholar working in Partch’s lab at the University of California, Santa Cruz, explained how a particular enzyme called a kinase, interacts with the Period protein. This interaction is through a process named phosphorylation, which involves the attachment of phosphate groups to the protein. This can occur at two different sites of the protein.

In the first area, called the ‘degron’ region, phosphorylation signals for the Period protein to be broken down, whereas in the second area, known as the FASP region, it serves to fortify the protein. The ratio between the protein’s breakdown and its reinforcement governs the duration of the biological clock cycle.

However, the occurrence of a mutation in the FASP region tends to favor the breakdown of the Period protein, consequently leading to a reduced clock cycle duration.

“There’s about a four-hour shortening of the clock when you have this FASP mutation,” Philpott adds.

A significant revelation from the latest research shows that a modified part of the protein FASP, known as the phosphorylated FASP region, acts as a brake on the action of an enzyme called a kinase. This self-regulating mechanism allows the protein Period to effectively control its own controller, decelerating the process of the degron region’s phosphorylation, and consequently extending the cycle.

In the words of the lead researcher Partch, “We need this pause button to slow down what would otherwise be very fast biochemistry.”

The researchers showed that the inhibition results from binding of the phosphorylated FASP region to a particular site on the kinase, which could potentially be targeted by a drug.” plag free

“We can start thinking about this as a tunable system,” Philpott adds. “We’ve identified regions on the kinase that are potentially targetable to tune its activity for therapeutic applications.”

Partch remarked that the majority of medications aimed at kinases operate by inhibiting the enzyme’s functional region.

“That’s basically a hammer that turns off the kinase activity,” she adds. “But with the discovery of new pockets unique to this kinase, we can target those to modulate its activity in a more controlled way.”

The potential applications of these findings could extend beyond aiding those suffering from Familial Advanced Sleep Phase Syndrome. Indeed, individuals whose sleep patterns are affected by inconsistent work shifts, travel across time zones, or other modern life stressors could also benefit significantly.

Another intriguing revelation from this recent research is that the Period protein’s feedback inhibition of the kinase enzyme is also observed in fruit flies. This is despite the fact that the sites of phosphorylation – the process by which the enzyme operates – differ between the two species.

“It turns out the short-cycle mutant in Drosophila, discovered in 1970, does the same thing as the short-cycle FASP mutation in humans,” Partch adds. “This mechanism has likely been in place throughout the evolution of multicellular animals. The fact that it’s been rooted in place for such a long time suggest it’s fundamental to making biological clocks on Earth have a 24-hour cycle.”

Partch and Philpott shared that their fruitful partnerships with various research labs across different institutions have expanded their capacity to investigate clock mechanisms from diverse perspectives. This research encompassed multiple methodologies, such as nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics simulations, and the utilization of specifically modified human cell lines. Furthermore, the study took a comparative approach, examining similar molecular processes in both humans and Drosophila fruit flies.

“It was a terrific collaborative team,” Partch adds.

Source: 10.1016/j.molcel.2023.04.019

Image Credit: Getty