Reversible Changes to Neural Proteins May Explain Sleep Need

Source: University of Tsukuba

Summary: Researchers at the International Institute for Integrative Sleep Medicine at Japan’s University of Tsukuba went looking for the biochemical changes that form the basis of this sleep-wake cycle.

Long periods of waking can lead to cognitive impairment, and the need to sleep continues to build up. Sleep then refreshes the brain through alterations in molecular biochemistry. These changes impact neuronal plasticity and brain function, but the molecular underpinnings of “sleepiness” are not well understood. A current theory of the sleep-wake cycle suggests that waking encodes memories, whereas sleep consolidates memories and restores synaptic homeostasis. Researchers from the University of Tsukuba suspected the molecular substrate of sleepiness should be seen in all brain regions, and should accumulate gradually during waking and dissipate through sleep. Their findings revealed that protein phosphorylation may be the key. They also found a dose-dependent increase in the number of phosphorylation events in the whole-brain phosphoproteome, which tracked increasing sleep need. The study findings were published I the journal Nature.

Addition of phosphoryl group to protein

By comparing the brains of sleep-deprived mice and Sleepy mutant mice, the phosphorylation of 80 proteins, named SNIPPs (Sleep-Need-Index-Phosphoproteins), was found to be increased along with sleep need. Credit: University of Tsukuba

During normal function, cellular proteins may be modified by the reversible addition of a chemical phosphoryl group, this is known as phosphorylation. The team used techniques for analyzing which proteins are phosphorylated and which are not. This enabled them to identify and quantify the phosphorylation of a wide range of brain proteins in sleep-deprived mice, and in mice with a single point mutation, named Sleepy, that increases both sleep time and sleep need. By analyzing the quantity of change in phosphorylation, they identified 80 proteins that are hyper-phosphorylated when the mouse is sleepy, which they termed the Sleep-Need-Index-PhosphoProteins (SNIPPs). The phospho-state of SNIPPs changed along with sleep need. Importantly, the SNIPPs identified were predominantly synaptic proteins. Given that the sleep-wake cycle impacts cognition, this research could aid in understanding sleep-wake patterns for optimal brain function.

Corresponding author, Masashi Yanagisawa, said “By comparing sleep-deprived mice and Sleepy mutant mice, we were able to filter out the effects of prolonged waking, prolonged sleeping and stress,” and further added, “Our findings show that the phosphorylation/dephosphorylation cycle of SNIPPs may be a major way that the brain regulates sleep-wake homeostasis.”

More Information: Zhiqiang Wang et al, “Quantitative phosphoproteomic analysis of the molecular substrates of sleep need”, Nature (2018). DOI: 10.1038/s41586-018-0218-8

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