Nature最新揭秘:人为何会“想睡觉”?
2018/06/15
人的一生有三分之一的时间在睡觉。那么,当我们产生睡意时,大脑中究竟发生了怎样的变化呢?近日,发表在Nature杂志上一篇论文给出了最新回答!


图片来源:Nature(https://doi.org/10.1038/s41586-018-0218-8)

6月13日发表的这项题为“Quantitative phosphoproteomic analysis of the molecular substrates of sleep need”的成果显示,蛋白质磷酸化可能是产生睡意的关键。

研究中,科学家们鉴定并量化了两类小鼠中多种不同的大脑蛋白质的磷酸化水平。其中一类是睡眠剥夺的小鼠(sleep-deprived mice),另一类是睡眠时间和睡眠需求都增加的突变小鼠(Sleepy mutant mice)。免疫化学和质谱分析结果显示,在两类小鼠的整个大脑中,蛋白质磷酸化增加的模式是相似的,且表现出了剂量依赖性。

“蛋白质功能可以通过位点特异性磷酸化来启动或关闭,也可以通过多位点的累积磷酸化来调节。因此,磷酸化模式可能能够揭示睡眠需求背后的分子机制。” 论文的第一作者Zhiqiang Wang解释道。


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

通过对磷酸化变化数量(quantity of change)的分析,研究人员确定了80种在小鼠困倦时过度磷酸化(hyper-phosphorylated)的蛋白质,并将这种蛋白命名为SNIPPs(Sleep-Need-Index-PhosphoProteins)。SNIPPs主要是突触蛋白,其磷酸化状态(phospho-state)会随睡眠需求发生改变。

研究还发现,长时间的觉醒会导致过度磷酸化(hyper-phosphorylation),而睡眠则会促进大脑蛋白质组的总体去磷酸化。考虑到睡眠-觉醒周期会影响认知,作者们认为,这项研究将帮助理解对应最佳大脑功能的睡眠-觉醒模式。

“我们的发现表明,SNIPPs的磷酸化/去磷酸化周期(phosphorylation/dephosphorylation cycle)可能是大脑调节睡眠-觉醒稳态的主要方式。”论文的共同通讯作者Masashi Yanagisawa总结道。

责编:风铃

参考资料:

Reversible changes to neural proteins may explain sleep need

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  • Quantitative phosphoproteomic analysis of the molecular substrates of sleep need

    Sleep and wake have global effects on brain physiology, from molecular changes1,2,3,4 and neuronal activities to synaptic plasticity3,4,5,6,7. Sleep–wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep8,9,10,11. 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 gene12, 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 synapses4,5,6. 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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