title: Early-onset sleep defects in Drosophila models of Huntington's disease reflect alterations of PKA/CREB signaling.
abstract: Huntington's disease (HD) is a progressive neurological disorder whose non-motor symptoms include sleep disturbances. Whether sleep and activity abnormalities are primary molecular disruptions of mutant Huntingtin (mutHtt) expression or result from neurodegeneration is unclear. Here, we report Drosophila models of HD exhibit sleep and activity disruptions very early in adulthood, as soon as sleep patterns have developed. Pan-neuronal expression of full-length or N-terminally truncated mutHtt recapitulates sleep phenotypes of HD patients: impaired sleep initiation, fragmented and diminished sleep, and nighttime hyperactivity. Sleep deprivation of HD model flies results in exacerbated sleep deficits, indicating that homeostatic regulation of sleep is impaired. Elevated PKA/CREB activity in healthy flies produces patterns of sleep and activity similar to those in our HD models. We were curious whether aberrations in PKA/CREB signaling were responsible for our early-onset sleep/activity phenotypes. Decreasing signaling through the cAMP/PKA pathway suppresses mutHtt-induced developmental lethality. Genetically reducing PKA abolishes sleep/activity deficits in HD model flies, restores the homeostatic response and extends median lifespan. In vivo reporters, however, show dCREB2 activity is unchanged, or decreased when sleep/activity patterns are abnormal, suggesting dissociation of PKA and dCREB2 occurs early in pathogenesis. Collectively, our data suggest that sleep defects may reflect a primary pathological process in HD, and that measurements of sleep and cAMP/PKA could be prodromal indicators of disease, and serve as therapeutic targets for intervention.
authors.affiliation: Department of Medical Genetics.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Gonzales
authors.affiliation: Neuroscience Training Program and.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Tanenhaus
authors.affiliation: Neuroscience Training Program and.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, 425-G Henry Mall, Madison, WI 53706, USA and.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Chaffee
authors.affiliation: Department of Medical Genetics, Department of Neurology, University of Wisconsin-Madison, 1685 Highland Ave., Madison, WI 53705-2281, USA jcyin@wisc.edu.
authors.forename: Jerry C P
authors.initials: JC
authors.lastname: Yin
mesh_terms: D017668:Age of Onset; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012890:Sleep / Q000235:genetics; D012893:Sleep Wake Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D029721:Drosophila Proteins; D051959:ELAV Proteins; C498009:ELAV protein, Drosophila; C557617:GAL4 protein, Drosophila; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases