Quantitative phosphoproteomic analysis of the molecular substrates of sleep need.
Quantitative phosphoproteomic analysis of the molecular substrates of sleep need.
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DOI：
10.1038/s41586-018-0218-8
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发表时间：
2018-06
期刊：
影响因子：
64.8
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Wang Z;Ma J;Miyoshi C;Li Y;Sato M;Ogawa Y;Lou T;Ma C;Gao X;Lee C;Fujiyama T;Yang X;Zhou S;Hotta-Hirashima N;Klewe-Nebenius D;Ikkyu A;Kakizaki M;Kanno S;Cao L;Takahashi S;Peng J;Yu Y;Funato H;Yanagisawa M;Liu Q
睡眠和觉醒对大脑生理学具有全局影响，从分子变化1，2，3，4和神经元活动到突触可塑性3，4，5，6，7。睡眠-觉醒稳态是通过产生睡眠需求来维持的，睡眠需求在清醒时积累，在睡眠时消散8，9，10，11。在这里，我们调查的分子基础的睡眠需要使用定量磷酸蛋白质组学分析的睡眠剥夺和睡眠增加的小鼠模型的睡眠需要。睡眠剥夺诱导大脑蛋白质组的累积磷酸化，其在睡眠期间消散。由于Sik 3基因12中的功能获得性突变，睡眠小鼠尽管睡眠量增加，但仍具有组成性的高睡眠需求。这些小鼠的大脑蛋白质组表现出过度磷酸化，类似于睡眠剥夺小鼠大脑中所见。两种模型的比较确定了80个主要的突触睡眠需要指数磷蛋白（SNIPPs），其中磷酸化状态密切平行的睡眠需要的变化。SLEEPY，突变的SIK 3蛋白，优先与SNIPPs结合并磷酸化。SIK 3活性的抑制降低了睡眠小鼠和睡眠剥夺的野生型小鼠在非快速眼动睡眠期间SNIPPs的磷酸化和慢波活性，这是睡眠需求的最佳可测量指标。我们的研究结果表明，SNIPP磷酸化的积累和消散与睡眠需要有关，因此SNIPP磷酸化是睡眠需要的分子特征。而清醒的增强突触编码的记忆，睡眠巩固记忆和恢复突触稳态的全局缩小兴奋性突触4，5，6。因此，SNIPPs的磷酸化-去磷酸化循环可能代表了突触稳态和睡眠-觉醒稳态的主要调节机制。
Sleep and wake have global effects on brain physiology, from molecular changes 1, 2, 3, 4 and neuronal activities to synaptic plasticity 3, 4, 5, 6, 7. Sleep–wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep 8, 9, 10, 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, 5, 6. Thus, the phosphorylation–dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep–wake homeostasis.
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影响因子：
14.9
作者：
Deutsch EW;Csordas A;Sun Z;Jarnuczak A;Perez-Riverol Y;Ternent T;Campbell DS;Bernal-Llinares M;Okuda S;Kawano S;Moritz RL;Carver JJ;Wang M;Ishihama Y;Bandeira N;Hermjakob H;Vizcaíno JA
通讯作者：
Vizcaíno JA
影响因子：
16.2
作者：
Boyken, Janina;Gronborg, Mads;Chua, John Jia En
通讯作者：
Chua, John Jia En
影响因子：
2.7
作者：
Benjamini, Yoav;Krieger, Abba M.;Yekutieli, Daniel
通讯作者：
Yekutieli, Daniel
影响因子：
64.8
作者：
Funato H;Miyoshi C;Fujiyama T;Kanda T;Sato M;Wang Z;Ma J;Nakane S;Tomita J;Ikkyu A;Kakizaki M;Hotta-Hirashima N;Kanno S;Komiya H;Asano F;Honda T;Kim SJ;Harano K;Muramoto H;Yonezawa T;Mizuno S;Miyazaki S;Connor L;Kumar V;Miura I;Suzuki T;Watanabe A;Abe M;Sugiyama F;Takahashi S;Sakimura K;Hayashi Y;Liu Q;Kume K;Wakana S;Takahashi JS;Yanagisawa M
通讯作者：
Yanagisawa M
DOI：
10.1126/science.aai8355
发表时间：
2017-02-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Diering GH;Nirujogi RS;Roth RH;Worley PF;Pandey A;Huganir RL
通讯作者：
Huganir RL