How Sleep Maintains Phosphoproteome Homeostasis?

Prolonged sleep deprivation (Pr-SD) is known to be lethal across many species. While several mechanisms linked to sleep regulation and the fatal consequences of sleep loss have been identified, the core molecular basis connecting Pr-SD lethality to sleep homeostasis in mammals has remained unclear.

Building on this, on June 24, 2025, Professor Zhiqiang Wang's research team from the School of Life Science and Technology, Harbin Institute of Technology, published a study in Cell Discovery titled: "Sleep prevents brain phosphoproteome disruption to safeguard survival." This research reveals that sleep prevents brain phosphoproteome disruption, thereby safeguarding survival.

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Overview

A key phenomenon highlighted by classic research is that during prolonged sleep deprivation, individuals enter an irreversible "point of no return (PONE)" state.

In a recent study, researchers used a prolonged sleep deprivation model and a reliable method to predict this PONE state. They found that mice in the PONE state couldn't enter natural sleep and showed significant disruption in their brain's phosphoproteome (the complete set of phosphorylated proteins). This disruption wasn't just about how long they were awake; it was directly linked to being in the PONE state.

The study also revealed that abnormal function of kinases (enzymes that add phosphates to proteins) or phosphatases (enzymes that remove them) in the brain accelerated the development of the PONE state and led to corresponding sleep abnormalities.

Crucially, just 80 minutes of recovery sleep each day significantly delayed the onset of the PONE state and restored the brain's phosphoproteome to a normal state. By combining recovery sleep with compensatory phosphatase expression, the harmful effects of excessive kinase activity on PONE development could be eliminated.

In summary, this research indicates that sleep is essential for maintaining the stability of the brain's phosphoproteome. Disruptions to this stability may not only contribute to the lethality caused by prolonged sleep deprivation but also impact normal sleep regulation mechanisms.

Fig.1 Assessment of PONE status during prolonged sleep deprivation.¹

Findings of the Study

This study reveals the crucial role of sleep in maintaining the stability of the brain's phosphoproteome, further clarifying, at a molecular level, sleep's protective function for survival and adaptation. The authors' findings may offer a new perspective on NREMS delta wave power and its potential representation of sleep homeostatic mechanisms, while also increasing our understanding of its importance.

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Reference

1. Ma, Jing et al. "Sleep prevents brain phosphoproteome disruption to safeguard survival." Cell discovery vol. 11,1 58. 24 Jun. 2025, doi:10.1038/s41421-025-00809-w. 7 Jun. 2025, doi:10.1038/s41386-025-02144-w. Distributed under Open Access license CC BY 4.0, without modification.