Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome

• Type of Material: Article
• Authors: Amanda A Freeman, Emory University; Elaine Pranski, Emory University; R. Daniel Miller, Emory University; Sara Radmard, Emory University; Douglas Bernhard, Emory University; Hyder A Jinnah, Emory University; Ranjita Betarbet, Emory University; David Rye, Emory University; Subhabrata Sanyal, Emory University
• Language: English
• Date: 2012-06-19
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cub.2012.04.027
• Title of Journal or Parent Work: Current Biology
• ISSN: 0960-9822
• Volume: 22
• Issue: 12
• Start Page: 1142
• End Page: 1148
• Grant/Funding Information: This work is supported by a FIRST fellowship and a Neurology NIH T32 fellowship to A.F. and Emory Neuroscience Initiative, Sleep Research Society and Restless Legs Foundation grants to S.S.
• Research Categories: Biology, Neuroscience; Biology, Cell

Abstract

Summary Restless Legs Syndrome (RLS), first chronicled by Willis in 1672 and described in more detail by Ekbom in 1945 [1], 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 [2,3]. While the pathophysiology of RLS is unknown, dopaminergic neurotransmission and deficits in iron availability modulate expressivity [1,4–9]. GWAS have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS [2,3,10–12]. 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.