title: Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.
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.
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Thi A
authors.initials: TA
authors.lastname: Tran
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Nguyen
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chang
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Lee
authors.forename: Malú G
authors.initials: MG
authors.lastname: Tansey
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein