Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.

Inflammation and oxidative stress have been implicated in the pathophysiology of Parkinson's disease (PD) and inhibition of microglial activation attenuates degeneration of dopaminergic (DA) neurons in animal models of PD. Loss-of-function mutations in the parkin gene, which encodes an E3 ubiqu...

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Autores principales:	Thi A Tran, Andrew D Nguyen, Jianjun Chang, Matthew S Goldberg, Jae-Kyung Lee, Malú G Tansey
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/19fbc2bad9e34893bfeb3afba3b13690
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spelling	oai:doaj.org-article:19fbc2bad9e34893bfeb3afba3b136902021-11-18T06:47:45ZLipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.1932-620310.1371/journal.pone.0023660https://doaj.org/article/19fbc2bad9e34893bfeb3afba3b136902011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21858193/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Inflammation and oxidative stress have been implicated in the pathophysiology of Parkinson's disease (PD) and inhibition of microglial activation attenuates degeneration of dopaminergic (DA) neurons in animal models of PD. Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, cause autosomal recessive parkinsonism. While most studies on Parkin have focused on its function in neurons, here we demonstrate that Parkin mRNA and protein is detectable in brain-resident microglia and peripheral macrophages. Using pharmacologic and genetic approaches, we found that Parkin levels are regulated by inflammatory signaling. Specifically, exposure to LPS or Tumor Necrosis Factor (TNF) induced a transient and dose-dependent decrease in Parkin mRNA and protein in microglia, macrophages and neuronal cells blockable by inhibitors of Nuclear Factor-Kappa B (NF-κB) signaling and not observed in MyD88-null cells. Moreover, using luciferase reporter assays, we identified an NF-κB response element in the mouse parkin promoter responsible for mediating the transcriptional repression, which was abrogated when the consensus sequence was mutated. Functionally, activated macrophages from Parkin-null mice displayed increased levels of TNF, IL-1β, and iNOS mRNA compared to wild type macrophages but no difference in levels of Nrf2, HO-1, or NQO1. One implication of our findings is that chronic inflammatory conditions may reduce Parkin levels and phenocopy parkin loss-of-function mutations, thereby increasing the vulnerability for degeneration of the nigrostriatal pathway and development of PD.Thi A TranAndrew D NguyenJianjun ChangMatthew S GoldbergJae-Kyung LeeMalú G TanseyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e23660 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thi A Tran Andrew D Nguyen Jianjun Chang Matthew S Goldberg Jae-Kyung Lee Malú G Tansey Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.
description	Inflammation and oxidative stress have been implicated in the pathophysiology of Parkinson's disease (PD) and inhibition of microglial activation attenuates degeneration of dopaminergic (DA) neurons in animal models of PD. Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, cause autosomal recessive parkinsonism. While most studies on Parkin have focused on its function in neurons, here we demonstrate that Parkin mRNA and protein is detectable in brain-resident microglia and peripheral macrophages. Using pharmacologic and genetic approaches, we found that Parkin levels are regulated by inflammatory signaling. Specifically, exposure to LPS or Tumor Necrosis Factor (TNF) induced a transient and dose-dependent decrease in Parkin mRNA and protein in microglia, macrophages and neuronal cells blockable by inhibitors of Nuclear Factor-Kappa B (NF-κB) signaling and not observed in MyD88-null cells. Moreover, using luciferase reporter assays, we identified an NF-κB response element in the mouse parkin promoter responsible for mediating the transcriptional repression, which was abrogated when the consensus sequence was mutated. Functionally, activated macrophages from Parkin-null mice displayed increased levels of TNF, IL-1β, and iNOS mRNA compared to wild type macrophages but no difference in levels of Nrf2, HO-1, or NQO1. One implication of our findings is that chronic inflammatory conditions may reduce Parkin levels and phenocopy parkin loss-of-function mutations, thereby increasing the vulnerability for degeneration of the nigrostriatal pathway and development of PD.
format	article
author	Thi A Tran Andrew D Nguyen Jianjun Chang Matthew S Goldberg Jae-Kyung Lee Malú G Tansey
author_facet	Thi A Tran Andrew D Nguyen Jianjun Chang Matthew S Goldberg Jae-Kyung Lee Malú G Tansey
author_sort	Thi A Tran
title	Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.
title_short	Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.
title_full	Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.
title_fullStr	Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.
title_full_unstemmed	Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.
title_sort	lipopolysaccharide and tumor necrosis factor regulate parkin expression via nuclear factor-kappa b.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/19fbc2bad9e34893bfeb3afba3b13690
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Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.

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