Molecular Mechanics that Drives Animals to Sleep

For a long time, a simplistic idea to know the mechanism that drives us to sleep with the amount of sleep we banked the night before had been unknown. Recently, researchers working in Japan, China, and the USA centred at Japan's University of Tsukuba find that a group of phosphoproteins accumulates when animals are awake and dissipates during sleep. This research work was carried out in mice. They described how sleep and wake have global effects on brain, from measuring the electrical voltage changes of the brain to explore brain waves during sleep, down to the effects on the single neuron, to how sleep changes communication between brain cells, and the global expression of genes in the brain.

The study was published in Nature describes how phosphorylation of just 80 proteins in the brain induce the need to sleep. What’s more, they show that these proteins are typically associated with synapses, the junctions between brain cells where cellular communication takes place. Naming these proteins, ‘sleep-need-index phosphoproteins’ (SNIPPs), they describe how the level of phosphorylation of these SNIPPs forms a molecular signature for the drive to sleep. 

They go on to describe how a mutant protein called SLEEPY preferentially associates with SNIPPs. It was found that the inhibition of the activity of SLEEPY and its normal variant in mice reduced phosphorylation of SNIPPS and reduced the drive to sleep. The researchers claim that this reduction in sleep drive was so powerful it also worked in sleep-deprived mice.

Their elaborated research work suggests that phosphorylating and dephosphorylating SNIPPs presents a major regulatory mechanism by which sleep homeostasis is achieved. Increasing phosphorylation of SNIPPs increases the drive to sleep, and SNIPP dephosphorylation decreases sleep drive. 

Study of the mechanisms that regulate circadian rhythms and sleep homeostasis at the level of protein phosphorylation is important. Findings from studies like this will not only inform our understanding of sleep/wake cycles but also shed light on the how brain physiology is affected throughout the 24-hour period, and could greatly influence human health. 

At last, this important finding exhibits that modulating SNIPP phosphorylation will be a viable therapeutic angle for treating insomnia or jetlag or mediating the health effects of shift work.

References:
1. Wang, Z. et al. Quantitative phosphoproteomic analysis of the molecular substrates of sleep need, Nature(June 2018 issue) 

2. Funato, H. et al. Forward-genetics analysis of sleep in randomly mutagenized mice. Nature 539, 378–383 (2016)