Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome.
Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome.
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DOI：
10.1016/j.cub.2012.04.027
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发表时间：
2012-06-19
期刊：
影响因子：
9.2
通讯作者：
Sanyal, Subhabrata
中科院分区：
文献类型：
--
作者：
Freeman, Amanda;Pranski, Elaine;Miller, R. Daniel;Radmard, Sara;Bernhard, Doug;Jinnah, H. A.;Betarbet, Ranjita;Rye, David B.;Sanyal, Subhabrata
不宁腿综合征（RLS）于1672年由Willis首次记录，1945年由Ekbom详细描述，是一种普遍存在的感觉运动神经障碍（占人口的5-10%），其昼夜节律偏好于傍晚和夜晚。典型的临床特征还包括在休息期间强烈的移动冲动，运动缓解，睡眠中的不自主运动（即睡眠时周期性的腿部运动）和碎片化睡眠。虽然RLS的病理生理机制尚不清楚，但多巴胺能神经传递和铁可用性缺陷可调节其表达。GWAS已经确定了6号染色体上BTBD9基因内含子区域的多态性，该多态性具有很大的RLS风险。在这里，我们报告了果蝇同源基因CG1826 （dBTBD9）的缺失明显扰乱了睡眠，并伴随着清醒和运动活动的增加。我们进一步表明，BTBD9调节果蝇的脑多巴胺水平，并通过人类细胞系中的铁调节蛋白-2 （IRP2）控制铁稳态。据我们所知，这是首次对一种“新颖的”或迄今为止知之甚少的基因进行反向遗传分析，该基因与一种极其常见和复杂的睡眠障碍有关，并建立了一种严密概括所有疾病表型的RLS动物模型。
Restless Legs Syndrome (RLS), first chronicled by Willis in 1672 and described in more detail by Ekbom in 1945, is a prevalent sensorimotor neurological disorder (5–10% in the population) with a circadian predilection for the evening and night. Characteristic clinical features also include a compelling urge to move during periods of rest, relief with movement, involuntary movements in sleep (viz., periodic leg movements of sleep), and fragmented sleep. While the pathophysiology of RLS is unknown, dopaminergic neurotransmission and deficits in iron availability modulate expressivity. GWAS have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS. Here, we report that loss of the Drosophila homolog CG1826 (dBTBD9) appreciably disrupts sleep with concomitant increases in waking and motor activity. We further show that BTBD9 regulates brain dopamine levels in flies and controls iron homeostasis through the iron regulatory protein-2 (IRP2) in human cell lines. To our knowledge, this represents the first reverse genetic analyses of a “novel” or heretofore poorly understood gene implicated in an exceedingly common and complex sleep disorder and the development of an RLS animal model that closely recapitulates all disease phenotypes.
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影响因子：
64.5
作者：
RUBIN, GM;KIDWELL, MG;BINGHAM, PM
通讯作者：
BINGHAM, PM
影响因子：
11.2
作者：
COLEMAN, RM;POLLAK, CP;WEITZMAN, ED
通讯作者：
WEITZMAN, ED
影响因子：
2
作者：
Hening
通讯作者：
Hening
影响因子：
3.7
作者：
Kong EC;Woo K;Li H;Lebestky T;Mayer N;Sniffen MR;Heberlein U;Bainton RJ;Hirsh J;Wolf FW
通讯作者：
Wolf FW
影响因子：
16.2
作者：
Stavropoulos N;Young MW
通讯作者：
Young MW