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

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Sleep Fragmentation and Motor Restlessness in a Drosophila Model of Restless Legs Syndrome View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology 22, 1142–1148, June 19, 2012 ª2012 Elsevier Ltd All rights reserved DOI 10.1016/j.cub.2012.04.027 Report Sleep Fragmentation and Motor Restlessness in a Drosophila Model of Restless Legs Syndrome Amanda Freeman,1,2 Elaine Pranski,2 R. Daniel Miller,2 reliable antibodies for dBTBD9 immunohistochemistry, we Sara Radmard,1 Doug Bernhard,2 H.A. Jinnah,2 followed transgenically expressed FLAG-tagged full-length Ranjita Betarbet,2 David B. Rye,2 and Subhabrata Sanyal1,2,* dBTBD9 and visualized Drosophila BTBD9 as distinct puncta 1Department of Cell Biology in neuronal cytoplasm (Figure 1L; Figure S1B). Taken together, 2Department of Neurology these results suggest that BTBD9 is a cytosolic protein that is Emory University School of Medicine, Atlanta, GA 30322, USA widely expressed in the nervous system. We hypothesized that BTBD9 belongs to a family of BTB domain-containing substrate adaptors for the cullin-3 (Cul-3) Summary class of E3 ubiquitin ligases [17] because homology modeling of both human and fly BTBD9 on the crystal structure of the Restless Legs Syndrome (RLS), first chronicled by Willis in MATH-BTB protein SPOP revealed the presence of a Cul-3 1672 and described in more detail by Ekbom in 1945 [1], is binding ‘‘3-box’’ motif [18](Figure 1G). Consistent with this a prevalent sensorimotor neurological disorder (5%–10% in idea, FLAG-tagged dBTBD9 shows extensive colocalization the population) with a circadian predilection for the evening with Drosophila GFP-tagged Cul-3 in neuronal soma (Fig- and night. Characteristic clinical features also include ure 1L). Interestingly, overexpression of dBTBD9 without a compelling urge to move during periods of rest, relief Cul-3 coexpression resulted in prominent aggregates that dis- with movement, involuntary movements in sleep (viz., peri- appeared in the presence of excess Cul-3 (Figures 1M and 1N; odic leg movements of sleep), and fragmented sleep [2, 3]. Figures S3C and S3D). These data support BTBD9’s function Although the pathophysiology of RLS is unknown, dopami- as a Cul-3 adaptor and suggest that stringent stoichiometric nergic neurotransmission and deficits in iron availability ratios between BTBD9 and Cul-3 might be maintained under modulate expressivity [1, 4–9]. Genome-wide association physiological conditions. studies have identified a polymorphism in an intronic region To examine phenotypic consequences resulting from loss of of the BTBD9 gene on chromosome 6 that confers substan- BTBD9, we isolated Drosophila mutants for dBTBD9 by tial risk for RLS [2, 3, 10–12]. Here, we report that loss of the excising a P element transposon inserted 47 base pairs Drosophila homolog CG1826 (dBTBD9) appreciably disrupts upstream of the dBTBD9 transcription start site (P{SUPor-P} sleep with concomitant increases in waking and motor CG1826KG07859) using standard genetic methods [19]. Two activity. We further show that BTBD9 regulates brain dopa- excision lines that carried large deletions in the dBTBD9 locus mine levels in flies and controls iron homeostasis through without affecting the adjacent genes Atg8a and CG15211 the iron regulatory protein-2 in human cell lines. To our were selected for analysis (Figure 2A). These viable alleles, knowledge, this represents the first reverse genetic analysis dBTBD9wlst1 and dBTBD9wlst2 (wlst is for ‘‘wanderlust’’ of a ‘‘novel’’ or heretofore poorly understood gene impli- because these animals show increased locomotor activity, cated in an exceedingly common and complex sleep see below), did not produce any detectable dBTBD9 mRNA disorder and the development of an RLS animal model that (Figure 1F) and were designated as null alleles. Both alleles closely recapitulates all disease phenotypes. had life spans that were significantly less than the genetically matched precise excision alleles that were used as controls Results and Discussion suggesting fitness deficits that result from the loss of dBTBD9 (Figure S2B). A number of genetic loci confer risk for Restless Legs Next, we monitored the Drosophila rest-activity cycle in Syndrome (RLS), including a SNP marker (rs3923809) in the dBTBD9 mutants using the Drosophila Activity Monitor gene BTBD9 that accounts for approximately 50% of the pop- (DAM) [20–22]. Although the total duration of sleep per 24 hr ulation-attributable risk [11–16]. To confirm these findings and period did not differ appreciably between control and mutant test the hypothesis that BTBD9 regulates sleep fragmentation, groups, the average bout lengths were decreased, the number we examined the behavioral and metabolic consequences of of sleep bouts increased, and the amount of wake after sleep disrupting BTBD9 function both in Drosophila and in human onset (WASO) increased (Figure 2B). Together, these pheno- cell lines. BTBD9 is expressed widely in the mammalian types are emblematic of fragmented night-time sleep in nervous system and in human embryonic kidney (HEK) cell dBTBD9 mutants, as demonstrated in hypnograms from lines (Figures 1A and 1B) and is a predominantly cytosolic individual flies (Figure 2D), which closely parallel the sleep protein (Figures 1C and 1H–1K). A survey throughout the rat continuity disruptions in RLS patients. These putative dBTBD9 central nervous system (CNS) reveals a widespread, yet mutations are allelic because they did not complement one specific, staining pattern for BTBD9 in circuits that regulate another—rather, no sleep phenotypes were observed in motor activity, memory, and emotion (Figures 1I–1K; see also heterozygotes (Figure S2A). Sleep phenotypes were unequiv- Figure S1A available online). CNS expression is conserved in ocally mapped to dBTBD9 because pan-neuronal add back C155 the Drosophila homolog dBTBD9 (CG1826) as seen with RT- of dBTBD9 (using the elav -GAL4 driver; [23, 24]) in a null PCR analysis of dBTBD9 messenger RNA (mRNA) and whole background rescued all sleep phenotypes (Figure 2B). Finally, head western blots (Figures 1D and 1E). In the absence of RNAi-mediated knockdown of dBTBD9 mRNA in the nervous system strongly phenocopied dBTBD9 null alleles (Figure 2C). These results clearly document sleep fragmentation in *Correspondence: [email protected] dBTBD9 mutants and indicate that neuronal dBTBD9 function Sleep Fragmentation in a Drosophila Model of RLS 1143 Figure 1. BTBD9 Is a Cytosolic Cullin-3 Adaptor that Is Expressed Widely in the Mammalian and Drosophila Nervous System (A) Western blots of two independent mouse and human brain protein extracts probed for BTBD9. (B) Protein extracts from HEK cells showing basal, overexpression, and small interfering RNA mediated knockdown of BTBD9. (C) HEK cell transfected with Myc-tagged BTBD9 and stained for BTBD9, Myc, and actin. Arrows indicate BTBD9 and Myc colocalization. (D) Western blots from Drosophila adult brain protein extracts probed for dBTBD9. dBTBD9 [8] is a precise excision control, dBTBD9[OE] is pan-neuronal overexpression of dBTBD9, and dBTBD9[wlst1] and dBTBD9[wlst2] are null alleles. (E) PCR using cDNA and genomic DNA extracted from the adult Drosophila brain as template with intron-spanning primers for dBTBD9. (F) RT-PCR from mRNA isolated from control and excision alleles of dBTBD9. The ribosomal gene rp49 is used as a control. (G) Homology model of the N-terminal half of BTBD9 based on the crystal structure of SPOP showing the Cul-3 interacting 3-box. (H–K) BTBD9 staining in human nucleus basalis demonstrates cytoplasmic localization. Scale bar represents 20 mm. BTBD9 staining (I) throughout the gray matter of the rat spinal cord including motor neurons (inset shows enlarged view), rat hippocampus (J) (enlarged inset shows neurons oftheCA1 region), and Purkinje cells(K) of thecere- bellum (inset shows enlarged view). Scale bar represents 200 mm in (I)–(K) and 20 mm (I)–(K) insets. (L) A single neuron in the adult fly CNS stained for dBTBD9 (FLAG-tagged dBTBD9) and Cul-3 (GFP-tagged Cul-3) showing extensive colocali- zation (arrows). Scale bar represents 2 mm. (M) CNS of an adult fly expressing FLAG-tagged dBTBD9 (enlarged inset shows dBTBD9 aggre- gates). (N) CNS of a fly expressing both dBTBD9 and Cul- 3, (inset shows enlarged view). Scale bar repre- sents 100 mm (see also Figure S1). is required for normal sleep architecture and consolidation homeostasis in RLS [3, 31–34]. In the mammalian brain, in Drosophila. BTBD9 is strongly expressed in dopaminergic neurons of the A key endophenotype of RLS is the presence of periodic substantia nigra and A11 neurons (Figure 3C). Although we limb movements (PLMs) in patients both during wakefulness could not determine dBTBD9 expression in fly dopaminergic and sleep [11, 25–27]. To evaluate motor behavior in dBTBD9 neurons, RNAi-mediated knockdown of dBTBD9 in large mutants, we measured flight and negative geotaxis, but these subsets of dopaminergic neurons (using either the tyrosine were normal (Figure S2C) [28]. However, when mutant flies hydroxylase (TH) or HL9-GAL4 driver; [35, 36]) reproduced were enclosed within a restricted space, they were hyperloco- dBTBD9 mutant sleep fragmentation phenotypes (Figures 3D motive (Figure 2E; Movie S1). This phenotype bears an and 3E). This is consistent with expression of these two uncanny resemblance to the ‘‘restlessness’’ observed in RLS GAL4 drivers in dopaminergic neurons that are presumed to patients asked to remain immobile in the ‘‘suggested immo- control locomotion [36]. Interestingly, we did not observe bility test’’ (SIT) [29]. Next, we turned to the visuomotor similar fragmentation when dBTBD9 was knocked down in Buridan’s assay [30] to measure locomotion with greater a more restricted subset of dopaminergic neurons using the analytical power. Such experiments revealed that mutant flies HL5-GAL4 line, a domain that does not influence ethanol- walked at the same speed as controls but spent more time induced hyperactivity [37](Figures 3D and 3E). Therefore, moving with fewer pauses (Figures 2F and 2G), resulting in either BTBD9 mediates sleep phenotypes by altering neuro- longer uninterrupted bouts of walking.
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