Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration
Department of Neurobiology; Hong-Sheng Li Lab
Neuroscience and Neurobiology
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 ATPalpha, an alpha 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 ATPalpha knockdown photoreceptors were already depolarized in the dark, which was due to a loss of intracellular K(+). Importantly, ATPalpha 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 beta subunit, partially reproduced the signaling and degenerative defects observed in ATPalpha 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.
ATPα, Neurodegeneration, nrv3
DOI of Published Version
Exp Neurol. 2014 Nov;261:791-801. doi: 10.1016/j.expneurol.2014.08.025. Epub 2014 Sep 7. Link to article on publisher's site
Luan, Zhuo; Reddig, Keith; and Li, Hong-Sheng, "Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration" (2014). Neurobiology Publications and Presentations. 171.