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Quantitative phosphoproteomic analysis of the molecular substrates of sleep need

机译：睡眠需求分子底物的磷酸化蛋白质组学定量分析

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摘要

Sleep and wake have global effects on brain physiology, from molecular changes(1-4) and neuronal activities to synaptic plasticity(2). Sleep-wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep(8-11). 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 synapses(4-6). Thus, the phosphorylation-dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep-wake homeostasis.
机译：从分子变化（1-4）和神经元活动到突触可塑性（2），睡眠和苏醒对大脑生理具有全局性影响。觉醒的体内平衡是通过在清醒时积累并在睡眠过程中消散的睡眠需求的产生而保持的（8-11）。在这里，我们通过对睡眠不足和睡眠需求增加的小鼠模型进行定量磷酸蛋白质组分析，研究了睡眠需求的分子基础。睡眠不足会诱发大脑蛋白质组的累积磷酸化，从而在睡眠过程中消散。由于Sik3基因的功能获得性突变，嗜睡小鼠尽管睡眠量增加，但仍具有很高的睡眠需求。这些小鼠的脑蛋白质组显示出过度磷酸化，类似于睡眠不足的小鼠的大脑中所见。两种模型的比较确定了80种主要为突触的睡眠需要指数磷蛋白（SNIPP），其中的磷酸化状态与睡眠需求的变化紧密相关。 SLEEPY，一种突变的SIK3蛋白，优先与SNIPPs结合并使其磷酸化。 SIK3活性的抑制会降低非快速眼动睡眠期间SNIPPs的磷酸化和慢波活性，这是睡眠小鼠和睡眠剥夺的野生型小鼠中睡眠需求最众所周知的可衡量指标。我们的研究结果表明，SNIPPs的磷酸化与睡眠需求有关，因此积累和消散，因此SNIPP磷酸化是睡眠需求的分子标志。醒来通过增强突触来编码记忆，而睡眠则通过全局降低兴奋性突触来巩固记忆并恢复突触的稳态（4-6）。因此，SNIPPs的磷酸化-去磷酸化周期可能代表了一个主要的调节机制，是突触稳态和觉醒稳态的基础。

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  • 来源
    《Nature》 |2018年第7710期|435-439|共5页
  • 作者

    Wang Zhiqiang; Ma Jing; Miyoshi Chika; Lie Yuxin; Sato Makito; Ogawa Yukino; Lou Tingting; Ma Chengyuan; Gao Xue; Lee Chiyu; Fujiyama Tomoyuki; Yang Xiaojie; Zhou Shuang; Hotta-Hirashima Noriko; Klewe-Nebenius Daniela; Ikkyu Aya; Kakizaki Miyo; Kanno Satomi; Cao Liqin; Takahashi Satoru; Peng Junmin; Yu Yonghao; Funato Hiromasa; Yanagisawa Masashi; Liu Qinghua;

  • 作者单位

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    St Jude Childrens Res Hosp, St Jude Prote Facil, Dept Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Natl Inst Biol Sci, Beijing, Peoples R China;

    Natl Inst Biol Sci, Beijing, Peoples R China;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Natl Inst Biol Sci, Beijing, Peoples R China;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Lab Anim Resource Ctr, Tsukuba, Ibaraki, Japan;

    St Jude Childrens Res Hosp, St Jude Prote Facil, Dept Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX USA;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

    Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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