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

Thi A Tran,Jianjun Chang,Matthew S Goldberg,Jae-Kyung Lee,Andrew D Nguyen,Malú G Tansey,Mark P Mattson

doi:10.1371/journal.pone.0023660

Thi A Tran, Jianjun Chang + Show 5 more

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https://doi.org/10.1371/journal.pone.0023660

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Abstract

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.

Highlights

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder affecting approximately 1–2% of the adult population over 65 years of age [1]
We investigated the extent to which Parkin is expressed in microglia and macrophages, cells involved in innate immunity
We found that Parkin mRNA and protein are detectable by real-time PCR and immunoblotting techniques respectively, in BV2 microglia, primary microglia and peritoneal macrophages (Figure 1)

Summary

Introduction

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder affecting approximately 1–2% of the adult population over 65 years of age [1]. Several lines of evidence implicate neuroinflammation as a contributing factor in PD pathogenesis [3,4,5,6]. PET imaging studies of PD patients show increased neuroinflammation as evidenced by microglial activation in brain regions most affected by PD compared to healthy, age-matched controls [7]. Neuroinflammation is largely characterized by activation of microglia [8]. These monocyte-derived brain resident macrophages are central players in innate immune responses in the brain. Environmental toxins, genetic mutations, traumatic brain injury, and infection are among the factors known to activate microglia [9,10]

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