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Can We Treat Circadian Rhythm Disruption in PWS? New Research Offers Hope

A new study from Dr. Reiter’s lab reveals how lab-grown cells from PWS patients respond to treatment for disrupted circadian rhythms.

Human beings have adapted to our planet's 24-hour days. The body goes through daily cycles that affect things like metabolism, physical functions, and mood—these 24-hour cycles are called the circadian rhythm.

What you may not know is that this adaptation affects processes at a more basic level than your brain. Even isolated cells growing in a lab follow rhythmic gene expression patterns on a 24-hour cycle, despite having no sense of day or night.

Sleep Disruption in PWS

Disruptions to circadian rhythms are linked to increased risk of obesity and mood disorders in the general population. In individuals with Prader-Willi syndrome (PWS), disrupted sleep, early waking, and excessive daytime sleepiness (EDS) are among the most commonly reported and difficult behaviors to manage. These symptoms are often associated with increased anxiety, depression, and other mental health challenges.

These behaviors and disrupted underlying circadian processes have long been apparent in PWS patients and several mouse models of PWS, but a new publication from Dr. Lawrence Reiter's lab at Tulane University, “Circadian Rhythm Defects in Prader-Willi Syndrome Neurons," reports a significant advancement in using isolated cells to understand and treat circadian defects in PWS cells, laying the foundation to potentially positively impact metabolism, physiology, and mental health in people with PWS.

Using Lab-Grown Cells to Study Circadian Disruption

Dr. Reiter has developed a technique to efficiently measure the circadian period of cells growing in a lab dish. This allows comparisons across multiple cell lines from individuals with PWS and other neurodevelopmental disorders.

Dr. Reiter found that some cells from PWS patients have a circadian period about one hour shorter than those from neurotypical individuals. Whether the donors of those cells experience more severe sleep-related symptoms remains to be determined.

This cell-based approach is also noteworthy for its ability to streamline testing to determine if drugs can affect these periods, a much more efficient way to screen compared to using mice or humans. 

Testing a Drug to Restore Circadian Timing

Having found PWS cells with short circadian periods, Dr. Reiter proceeded to expose these cells to a drug known to lengthen circadian period: Longdaysin. The drug was able to rescue the short PWS period length to control levels, providing evidence that we may be able to correct this dysfunction in patients through medication.

Dr. Reiter's cell-based assay will be integral to finding the drugs that are most effective in correcting altered circadian periods.

What’s the Role of the MAGEL2 Gene?

How does PWS genetics cause these disrupted circadian rhythms? The authors suggest that the disruption is likely due to the deletion of the MAGEL2 gene in PWS, as several earlier studies have suggested it plays a role in fine-tuning the circadian rhythm.

If that is the case, individuals with the closely related Schaaf-Yang syndrome (SYS), caused by mutations just in the MAGEL2 gene, could also benefit from these advancements, as they also experience sleep problems identified by parents as a very important issue in the majority of individuals.

How Families Are Advancing This Research

The cells used in these experiments are extracted from baby teeth naturally lost by children with PWS and SYS. A special thank you to all of the families who have sent their ‘baby teeth’ to Dr. Reiter’s group, which allowed this study to be completed!

If you have a child with PWS or SYS in this age group, you can help support continued research by donating. More information can be found here.

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Topics: Research, Sleep

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