Sleep Fragmentation and Motor Restlessness in a Drosophila Model of Restless Legs Syndrome

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• 作者：Amanda Freeman¹ ; ² ; Elaine Pranski² ; R.  ; Daniel Miller² ; Sara Radmard¹ ; Doug Bernhard² ; H.A. Jinnah² ; Ranjita Betarbet² ; David  ; B. Rye² ; Subhabrata Sanyal¹ ; ² ; ^{ssanya2@emory.edu}
• 刊名：Current Biology
• 出版年：2012
• 期刊代码：2_09609822
• 类别：abs
• 出版时间：19 June, 2012
• 卷：22
• 期：12
• 页码：1142-1148
• 文件大小：1349 K

摘要

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Summary

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 []. Although the pathophysiology of RLS is unknown, dopaminergic neurotransmission and deficits in iron availability modulate expressivity []. Genome-wide association studies have identified a polymorphism in an intronic region of the m>BTBD9m> gene on chromosome 6 that confers substantial risk for RLS []. Here, we report that loss of the m>Drosophilam> homolog m>CG1826m> (m>dBTBD9m>) 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 in human cell lines. To our knowledge, this represents the first reverse genetic analysis of a 鈥渘ovel鈥?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.