title: Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration.
abstract: The activity of Na(+)/K(+)-ATPase establishes transmembrane ion gradients and is essential to cell function and survival. Either dysregulation or deficiency of neuronal Na(+)/K(+)-ATPase has been implicated in the pathogenesis of many neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and rapid-onset dystonia Parkinsonism. However, genetic evidence that directly links neuronal Na(+)/K(+)-ATPase deficiency to in vivo neurodegeneration has been lacking. In this study, we use Drosophila photoreceptors to investigate the cell-autonomous effects of neuronal Na(+)/K(+) ATPase. Loss of ATPα, an α subunit of Na(+)/K(+)-ATPase, in photoreceptors through UAS/Gal4-mediated RNAi eliminated the light-triggered depolarization of the photoreceptors, rendering the fly virtually blind in behavioral assays. Intracellular recordings indicated that ATPα knockdown photoreceptors were already depolarized in the dark, which was due to a loss of intracellular K(+). Importantly, ATPα knockdown resulted in the degeneration of photoreceptors in older flies. This degeneration was independent of light and showed characteristics of apoptotic/hybrid cell death as observed via electron microscopy analysis. Loss of Nrv3, a Na(+)/K(+)-ATPase β subunit, partially reproduced the signaling and degenerative defects observed in ATPα knockdown flies. Thus, the loss of Na(+)/K(+)-ATPase not only eradicates visual function but also causes age-dependent degeneration in photoreceptors, confirming the link between neuronal Na(+)/K(+) ATPase deficiency and in vivo neurodegeneration. This work also establishes Drosophila photoreceptors as a genetic model for studying the cell-autonomous mechanisms underlying neuronal Na(+)/K(+) ATPase deficiency-mediated neurodegeneration.
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: Zhuo.Luan@umassmed.edu.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Luan
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Reddig
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: Hong-Sheng.Li@umassmed.edu.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Li
mesh_terms: D000375:Aging; D000818:Animals; D030801:Animals, Genetically Modified; D001766:Blindness / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004596:Electroretinography; D045604:Extracellular Fluid / Q000378:metabolism; D008027:Light / Q000009:adverse effects; D046529:Microscopy, Electron, Transmission; D009900:Optic Nerve / Q000473:pathology; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism* / Q000648:ultrastructure; D011188:Potassium / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D014785:Vision, Ocular / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; C550918:Nrv3 protein, Drosophila; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium
keywords: ATPα; Neurodegeneration; nrv3