Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.

Environmental exposure to manganese (Mn) leads to a neurodegenerative disease that has shared clinical characteristics with Parkinson's disease (PD). Mn-induced neurotoxicity is time- and dose-dependent, due in part to oxidative stress. We ascertained the molecular targets involved in Mn-induce...

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Autores principales:	Vernat Exil, Li Ping, Yingchun Yu, Sudipta Chakraborty, Samuel W Caito, K Sam Wells, Pratap Karki, Eunsook Lee, Michael Aschner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bba6e2a186de4cc785a041da88e5a646
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spelling	oai:doaj.org-article:bba6e2a186de4cc785a041da88e5a6462021-11-18T08:20:57ZActivation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.1932-620310.1371/journal.pone.0094753https://doaj.org/article/bba6e2a186de4cc785a041da88e5a6462014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24787138/?tool=EBIhttps://doaj.org/toc/1932-6203Environmental exposure to manganese (Mn) leads to a neurodegenerative disease that has shared clinical characteristics with Parkinson's disease (PD). Mn-induced neurotoxicity is time- and dose-dependent, due in part to oxidative stress. We ascertained the molecular targets involved in Mn-induced neurodegeneration using astrocyte culture as: (1) Astrocytes are vital for information processing within the brain, (2) their redox potential is essential in mitigating reactive oxygen species (ROS) levels, and (3) they are targeted early in the course of Mn toxicity. We first tested protein levels of Mn superoxide dismutase -2 (SOD-2) and glutathione peroxidase (GPx-1) as surrogates of astrocytic oxidative stress response. We assessed levels of the forkhead winged-helix transcription factor O (FoxO) in response to Mn exposure. FoxO is highly regulated by the insulin-signaling pathway. FoxO mediates cellular responses to toxic stress and modulates adaptive responses. We hypothesized that FoxO is fundamental in mediating oxidative stress response upon Mn treatment, and may be a biomarker of Mn-induced neurodegeneration. Our results indicate that 100 or 500 µM of MnCl2 led to increased levels of FoxO (dephosphorylated and phosphorylated) compared with control cells (P<0.01). p-FoxO disappeared from the cytosol upon Mn exposure. Pre-treatment of cultured cells with (R)-(-)-2-oxothiazolidine-4-carboxylic acid (OTC), a cysteine analog rescued the cytosolic FoxO. At these concentrations, MAPK phosphorylation, in particular p38 and ERK, and PPAR gamma coactivator-1 (PGC-1) levels were increased, while AKT phosphorylation remained unchanged. FoxO phosphorylation level was markedly reduced with the use of SB203580 (a p38 MAPK inhibitor) and PD98059 (an ERK inhibitor). We conclude that FoxO phosphorylation after Mn exposure occurs in parallel with, and independent of the insulin-signaling pathway. FoxO levels and its translocation into the nucleus are part of early events compensating for Mn-induced neurotoxicity and may serve as valuable targets for neuroprotection in the setting of Mn-induced neurodegeneration.Vernat ExilLi PingYingchun YuSudipta ChakrabortySamuel W CaitoK Sam WellsPratap KarkiEunsook LeeMichael AschnerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 5, p e94753 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vernat Exil Li Ping Yingchun Yu Sudipta Chakraborty Samuel W Caito K Sam Wells Pratap Karki Eunsook Lee Michael Aschner Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.
description	Environmental exposure to manganese (Mn) leads to a neurodegenerative disease that has shared clinical characteristics with Parkinson's disease (PD). Mn-induced neurotoxicity is time- and dose-dependent, due in part to oxidative stress. We ascertained the molecular targets involved in Mn-induced neurodegeneration using astrocyte culture as: (1) Astrocytes are vital for information processing within the brain, (2) their redox potential is essential in mitigating reactive oxygen species (ROS) levels, and (3) they are targeted early in the course of Mn toxicity. We first tested protein levels of Mn superoxide dismutase -2 (SOD-2) and glutathione peroxidase (GPx-1) as surrogates of astrocytic oxidative stress response. We assessed levels of the forkhead winged-helix transcription factor O (FoxO) in response to Mn exposure. FoxO is highly regulated by the insulin-signaling pathway. FoxO mediates cellular responses to toxic stress and modulates adaptive responses. We hypothesized that FoxO is fundamental in mediating oxidative stress response upon Mn treatment, and may be a biomarker of Mn-induced neurodegeneration. Our results indicate that 100 or 500 µM of MnCl2 led to increased levels of FoxO (dephosphorylated and phosphorylated) compared with control cells (P<0.01). p-FoxO disappeared from the cytosol upon Mn exposure. Pre-treatment of cultured cells with (R)-(-)-2-oxothiazolidine-4-carboxylic acid (OTC), a cysteine analog rescued the cytosolic FoxO. At these concentrations, MAPK phosphorylation, in particular p38 and ERK, and PPAR gamma coactivator-1 (PGC-1) levels were increased, while AKT phosphorylation remained unchanged. FoxO phosphorylation level was markedly reduced with the use of SB203580 (a p38 MAPK inhibitor) and PD98059 (an ERK inhibitor). We conclude that FoxO phosphorylation after Mn exposure occurs in parallel with, and independent of the insulin-signaling pathway. FoxO levels and its translocation into the nucleus are part of early events compensating for Mn-induced neurotoxicity and may serve as valuable targets for neuroprotection in the setting of Mn-induced neurodegeneration.
format	article
author	Vernat Exil Li Ping Yingchun Yu Sudipta Chakraborty Samuel W Caito K Sam Wells Pratap Karki Eunsook Lee Michael Aschner
author_facet	Vernat Exil Li Ping Yingchun Yu Sudipta Chakraborty Samuel W Caito K Sam Wells Pratap Karki Eunsook Lee Michael Aschner
author_sort	Vernat Exil
title	Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.
title_short	Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.
title_full	Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.
title_fullStr	Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.
title_full_unstemmed	Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.
title_sort	activation of mapk and foxo by manganese (mn) in rat neonatal primary astrocyte cultures.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/bba6e2a186de4cc785a041da88e5a646
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Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.

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