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Published on: June 13, 2025
Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis
Stephen Beesley1, Dae Wook Kim2, Matthew D'Alessandro1
1Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306.
Abstract:
The circadian clock is based on a transcriptional feedback loop with an essential time delay before feedback inhibition. Previous work has shown that PERIOD (PER) proteins generate circadian time cues through rhythmic nuclear accumulation of the inhibitor complex and subsequent interaction with the activator complex in the feedback loop. Although this temporal manifestation of the feedback inhibition is the direct consequence of PER's cytoplasmic trafficking before nuclear entry, how this spatial regulation of the pacemaker affects circadian timing has been largely unexplored. Here we show that circadian rhythms, including wake-sleep cycles, are lengthened and severely unstable if the cytoplasmic trafficking of PER is disrupted by any disease condition that leads to increased congestion in the cytoplasm. Furthermore, we found that the time delay and robustness in the circadian clock are seamlessly generated by delayed and collective phosphorylation of PER molecules, followed by synchronous nuclear entry. These results provide clear mechanistic insight into why circadian and sleep disorders arise in such clinical conditions as metabolic and neurodegenerative diseases and aging, in which the cytoplasm is congested.
Insights
Disruptions in PERIOD protein trafficking, common in diseases, destabilize circadian rhythms. Delayed phosphorylation and synchronous nuclear entry are key to the clock's timing and robustness.
Area of Science:
- Chronobiology
- Molecular Biology
- Cellular Biology
Background:
- The circadian clock relies on a transcriptional feedback loop with a critical time delay.
- PERIOD (PER) proteins regulate circadian timing via rhythmic nuclear accumulation and interaction with feedback loop complexes.
- The spatial regulation of PER protein trafficking before nuclear entry is crucial for circadian timing but underexplored.
Purpose of the Study:
- To investigate the impact of disrupted cytoplasmic trafficking of PER proteins on circadian rhythms.
- To elucidate the mechanisms underlying the time delay and robustness of the circadian clock.
- To connect cytoplasmic congestion in diseases to circadian and sleep disorders.
Main Methods:
- Studied the effects of disrupted PER protein cytoplasmic trafficking on circadian rhythms, including wake-sleep cycles.
- Investigated the role of PER protein phosphorylation and nuclear entry in generating circadian time delays and robustness.
- Utilized models of disease conditions causing cytoplasmic congestion.
Main Results:
- Disruption of PER protein cytoplasmic trafficking leads to lengthened and unstable circadian rhythms.
- Delayed and collective phosphorylation of PER proteins, followed by synchronous nuclear entry, generates the circadian clock's time delay and robustness.
- Cytoplasmic congestion, observed in metabolic diseases, neurodegenerative diseases, and aging, directly impacts circadian timing.
Conclusions:
- Circadian and sleep disorders observed in aging and various diseases are mechanistically linked to cytoplasmic congestion.
- The spatial and temporal regulation of PER protein trafficking is essential for maintaining stable circadian rhythms.
- Understanding PER protein dynamics offers insights into treating circadian dysfunction.
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