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

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 developme...

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Autores principales:	Yaping Sun, Zhiqiang Dong, Hadie Khodabakhsh, Sandip Chatterjee, Su Guo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2b4a889834bc4e1b980ece7728941b46
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spelling	oai:doaj.org-article:2b4a889834bc4e1b980ece7728941b462021-11-18T07:20:49ZZebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.1932-620310.1371/journal.pone.0035645https://doaj.org/article/2b4a889834bc4e1b980ece7728941b462012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22563390/?tool=EBIhttps://doaj.org/toc/1932-6203Parkinson'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.Yaping SunZhiqiang DongHadie KhodabakhshSandip ChatterjeeSu GuoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 4, p e35645 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yaping Sun Zhiqiang Dong Hadie Khodabakhsh Sandip Chatterjee Su Guo Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.
description	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.
format	article
author	Yaping Sun Zhiqiang Dong Hadie Khodabakhsh Sandip Chatterjee Su Guo
author_facet	Yaping Sun Zhiqiang Dong Hadie Khodabakhsh Sandip Chatterjee Su Guo
author_sort	Yaping Sun
title	Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.
title_short	Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.
title_full	Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.
title_fullStr	Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.
title_full_unstemmed	Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.
title_sort	zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/2b4a889834bc4e1b980ece7728941b46
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Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.

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