Quantitative phosphoproteomic analysis of the molecular substrates of sleep need

Zhiqiang Wang, Jing Ma, Chika Miyoshi, Yuxin Li, Makito Sato, Yukino Ogawa, Tingting Lou, Chengyuan Ma, Xue Gao, Chiyu Lee, Tomoyuki Fujiyama, Xiaojie Yang, Shuang Zhou, Noriko Hotta-Hirashima, Daniela Klewe-Nebenius, Aya Ikkyu, Miyo Kakizaki, Satomi Kanno, Liqin Cao, Satoru Takahashi, Junmin Peng, Yonghao Yu, Hiromasa Funato (), Masashi Yanagisawa () and Qinghua Liu ()
Additional contact information
Zhiqiang Wang: University of Tsukuba
Jing Ma: University of Tsukuba
Chika Miyoshi: University of Tsukuba
Yuxin Li: St. Jude Children’s Research Hospital
Makito Sato: University of Tsukuba
Yukino Ogawa: University of Tsukuba
Tingting Lou: University of Tsukuba
Chengyuan Ma: National Institute of Biological Sciences
Xue Gao: National Institute of Biological Sciences
Chiyu Lee: University of Tsukuba
Tomoyuki Fujiyama: University of Tsukuba
Xiaojie Yang: University of Tsukuba
Shuang Zhou: National Institute of Biological Sciences
Noriko Hotta-Hirashima: University of Tsukuba
Daniela Klewe-Nebenius: University of Tsukuba
Aya Ikkyu: University of Tsukuba
Miyo Kakizaki: University of Tsukuba
Satomi Kanno: University of Tsukuba
Liqin Cao: University of Tsukuba
Satoru Takahashi: University of Tsukuba
Junmin Peng: St. Jude Children’s Research Hospital
Yonghao Yu: University of Texas Southwestern Medical Center
Hiromasa Funato: University of Tsukuba
Masashi Yanagisawa: University of Tsukuba
Qinghua Liu: University of Tsukuba

Nature, 2018, vol. 558, issue 7710, 435-439

Abstract: Abstract Sleep and wake have global effects on brain physiology, from molecular changes1–4 and neuronal activities to synaptic plasticity3–7. Sleep–wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep8–11. Here we investigate the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and Sleepy mouse models of increased sleep need. Sleep deprivation induces cumulative phosphorylation of the brain proteome, which dissipates during sleep. Sleepy mice, owing to a gain-of-function mutation in the Sik3 gene 12 , have a constitutively high sleep need despite increased sleep amount. The brain proteome of these mice exhibits hyperphosphorylation, similar to that seen in the brain of sleep-deprived mice. Comparison of the two models identifies 80 mostly synaptic sleep-need-index phosphoproteins (SNIPPs), in which phosphorylation states closely parallel changes of sleep need. SLEEPY, the mutant SIK3 protein, preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation of SNIPPs and slow wave activity during non-rapid-eye-movement sleep, the best known measurable index of sleep need, in both Sleepy mice and sleep-deprived wild-type mice. Our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and therefore SNIPP phosphorylation is a molecular signature of sleep need. Whereas waking encodes memories by potentiating synapses, sleep consolidates memories and restores synaptic homeostasis by globally downscaling excitatory synapses4–6. Thus, the phosphorylation–dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep–wake homeostasis.

Date: 2018
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DOI: 10.1038/s41586-018-0218-8

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