Scientists Uncover Key Mechanism Behind Inherited Sleep Disorder

In a study published in Molecular Cell, scientists from UC Santa Cruz have revealed important details into the molecular interactions underlying Familial Advanced Sleep Phase Syndrome (FASP), an inherited sleep disorder. FASP causes individuals to become extreme "morning larks" due to their internal clocks operating on a 20-hour cycle instead of aligning with the standard 24-hour cycle of our planet.

Carrie Partch, corresponding author of the study, describes FASP as akin to permanent jet lag, as individuals with this disorder never fully adjust to the daylength. Despite the discovery of the FASP mutation 20 years ago and its significant impact on sleep patterns, the underlying mechanism behind this disorder remained unknown until now.

The FASP mutation affects one of the core clock proteins called Period, leading to a change in a single amino acid within the protein's structure. The recent study elucidates how this single alteration disrupts the interaction between the Period protein and a kinase enzyme called casein kinase 1. Consequently, the stability of the Period protein decreases, resulting in the shortening of an important step in the clock cycle.

Jonathan Philpott, first author of the study, explains that the kinase enzyme regulates the Period protein by adding phosphate groups through phosphorylation. There are two distinct regions within the protein where phosphorylation can occur: the "degron" region, which tags the Period protein for degradation, and the FASP region, which stabilizes it. The balance between degradation and stabilization determines the length of the clock cycle, and the FASP mutation disrupts this balance, favoring degradation of the Period protein and shortening the cycle by approximately four hours.

Crucially, the study reveals that the phosphorylated FASP region inhibits the activity of the kinase enzyme. This feedback inhibition mechanism allows Period to effectively regulate its own regulator, slowing down the phosphorylation of the degron region and lengthening the clock cycle. Partch emphasizes the necessity of this "pause button" to mitigate what would otherwise be an excessively rapid biochemical process.

Remarkably, the researchers demonstrate that the inhibition occurs due to the binding of the phosphorylated FASP region to a specific site on the kinase enzyme, which potentially opens avenues for targeted drug interventions.

Philpott highlights the potential of this discovery, stating that the regions on the kinase enzyme identified in this study could be targeted to modulate its activity for therapeutic applications. Unlike conventional kinase-targeting drugs that block the enzyme's active site, this approach would offer a more controlled and fine-tunable modulation of its activity.

The implications extend beyond individuals with Familial Advanced Sleep Phase Syndrome. The findings offer hope for individuals whose sleep cycles are disrupted by shift work, jet lag, and the challenges of modern life.

The study also uncovers a striking similarity in the feedback inhibition mechanism between humans and fruit flies, even though the phosphorylation sites differ. Partch suggests that this mechanism has likely existed throughout the evolution of multicellular organisms, indicating its fundamental role in establishing 24-hour biological clocks on Earth.