Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.

PloS One
Yaping SunSu Guo

Abstract

Parkinson's disease is a neurodegenerative disorder characterized by the prominent degeneration of dopaminergic (DA) neurons among other cell types. Here we report a first chemical screen of over 5,000 compounds in zebrafish, aimed at identifying small molecule modulators of DA neuron development or survival. We find that Neriifolin, a member of the cardiac glycoside family of compounds, impairs survival but not differentiation of both zebrafish and mammalian DA neurons. Cardiac glycosides are inhibitors of Na(+)/K(+) ATPase activity and widely used for treating heart disorders. Our data suggest that Neriifolin impairs DA neuronal survival by targeting the neuronal enriched Na(+)/K(+) ATPase α3 subunit (ATP1A3). Modulation of ionic homeostasis, knockdown of p53, or treatment with antioxidants protects DA neurons from Neriifolin-induced death. These results reveal a previously unknown effect of cardiac glycosides on DA neuronal survival and suggest that it is mediated through ATP1A3 inhibition, oxidative stress, and p53. They also elucidate potential approaches for counteracting the neurotoxicity of this valuable class of medications.

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Citations

Feb 13, 2013·The Journal of Biological Chemistry·Canan DoğanliKarin Lykke-Hartmann
Jan 17, 2014·Journal of Chemical Biology·Wei XuanIve De Smet
Feb 26, 2016·Frontiers in Endocrinology·Ana Maria OrellanaCristoforo Scavone
Oct 5, 2013·Neuroscience and Biobehavioral Reviews·Canan DoğanliKarin Lykke-Hartmann
Jul 10, 2020·CNS & Neurological Disorders Drug Targets·Nor H M NajibSeong L Teoh

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Methods Mentioned

BETA
transgenic
antisense oligonucleotide
confocal microscopy

Software Mentioned

InCell Developer
ImageJ
InCell

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