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Cullin-3介导的泛素化在睡眠和昼夜节律中的新作用:来自果蝇的见解

An emerging role for Cullin-3 mediated ubiquitination in sleep and circadian rhythm: insights from Drosophila.

作者信息

Freeman Amanda A H, Mandilaras Konstantinos, Missirlis Fanis, Sanyal Subhabrata

机构信息

Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.

出版信息

Fly (Austin). 2013 Jan-Mar;7(1):39-43. doi: 10.4161/fly.23506. Epub 2013 Jan 1.

DOI:10.4161/fly.23506
PMID:23455037
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3660749/
Abstract

Although the neurophysiological correlates of sleep have been thoroughly described, genetic mechanisms that control sleep architecture, long surmised from ethological studies, family histories and clinical observations, have only been investigated during the past decade. Key contributions to the molecular understanding of sleep have come from studies in Drosophila, benefitting from a strong history of circadian rhythm research. For instance, a number of recent papers have highlighted the role of the E3 ubiquitin ligase Cullin-3 in the regulation of circadian rhythm and sleep. We propose that different Cullin-3 substrate adaptors may affect specific molecular pathways and diverse aspects of circadian rhythm and sleep. We have previously shown that mutations in BTBD9, a risk factor for Restless Legs Syndrome (RLS) encoding a Cullin-3 substrate adaptor, lead to reduced dopamine, increased locomotion and sleep fragmentation. Here, we propose that Cullin-3 acts together with BTBD9 to limit the accumulation of iron regulatory proteins in conditions of iron deficiency. Our model is consistent with clinical observations implicating iron homeostasis in the pathophysiology of RLS and predicts that lack of BTBD9 leads to misregulation of cellular iron storage, inactivating the critical biosynthetic enzyme Tyrosine Hydroxylase in dopaminergic neurons, with consequent phenotypic effects on sleep.

摘要

尽管睡眠的神经生理相关性已得到充分描述,但从行为学研究、家族病史和临床观察中长期推测出的控制睡眠结构的遗传机制,仅在过去十年中才得到研究。对睡眠分子理解的关键贡献来自于对果蝇的研究,这得益于昼夜节律研究的悠久历史。例如,最近的一些论文强调了E3泛素连接酶Cullin-3在昼夜节律和睡眠调节中的作用。我们提出,不同的Cullin-3底物衔接蛋白可能会影响特定的分子途径以及昼夜节律和睡眠的不同方面。我们之前已经表明,不安腿综合征(RLS)的一个风险因素BTBD9发生突变,该基因编码一种Cullin-3底物衔接蛋白,会导致多巴胺减少、运动增加和睡眠碎片化。在此,我们提出Cullin-3与BTBD9共同作用,在缺铁条件下限制铁调节蛋白的积累。我们的模型与将铁稳态与RLS病理生理学相关联的临床观察结果一致,并预测BTBD9的缺失会导致细胞铁储存的调节异常,使多巴胺能神经元中的关键生物合成酶酪氨酸羟化酶失活,从而对睡眠产生表型影响。

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本文引用的文献

1
Ferritin is the key to dietary iron absorption and tissue iron detoxification in Drosophila melanogaster.铁蛋白是黑腹果蝇膳食铁吸收和组织铁解毒的关键。
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Identification of a dopamine pathway that regulates sleep and arousal in Drosophila.在果蝇中鉴定出一条调节睡眠和觉醒的多巴胺通路。
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Cul3 and the BTB adaptor insomniac are key regulators of sleep homeostasis and a dopamine arousal pathway in Drosophila.Cul3 和 BTB 接头失眠果蝇是睡眠内稳态和多巴胺觉醒途径的关键调节因子。
PLoS Genet. 2012;8(10):e1003003. doi: 10.1371/journal.pgen.1003003. Epub 2012 Oct 4.
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Genes for iron metabolism influence circadian rhythms in Drosophila melanogaster.铁代谢基因影响果蝇的昼夜节律。
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CULLIN-3 controls TIMELESS oscillations in the Drosophila circadian clock.CULLIN-3 控制果蝇生物钟中 TIMLESS 的振荡。
PLoS Biol. 2012;10(8):e1001367. doi: 10.1371/journal.pbio.1001367. Epub 2012 Aug 7.
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Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice.Btbd9 突变小鼠出现运动不安、睡眠障碍、热感觉改变和血清铁水平升高。
Hum Mol Genet. 2012 Sep 15;21(18):3984-92. doi: 10.1093/hmg/dds221. Epub 2012 Jun 7.
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Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome.果蝇不宁腿综合征模型中的睡眠碎片化和运动不安。
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Video tracking and analysis of sleep in Drosophila melanogaster.果蝇睡眠的视频跟踪与分析。
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