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Exp Neurol. 2014 Nov;261:791-801. doi: 10.1016/j.expneurol.2014.08.025. Epub 2014 Sep 7.

Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration.

Author information

1
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: Zhuo.Luan@umassmed.edu.
2
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: Hong-Sheng.Li@umassmed.edu.

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.

KEYWORDS:

ATPα; Neurodegeneration; nrv3

PMID:
25205229
PMCID:
PMC4194232
DOI:
10.1016/j.expneurol.2014.08.025
[Indexed for MEDLINE]
Free PMC Article

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