title: Minimally Toxic Dose of Lipopolysaccharide and α-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation.
abstract: The aim of this study is to investigate the role and mechanism of microglial NOX2 activation in minimally toxic dose of LPS and Syn-elicited synergistic dopaminergic neurodegeneration. NOX2+/+and NOX2-/-mice and multiple primary cultures were treated with LPS and/or Syn in vivo and in vitro. Neuronal function and morphology were evaluated by uptake of related neurotransmitter and immunostaining with specific antibody. Levels of superoxide, intracellular reactive oxygen species, mRNA and protein of relevant molecules, and dopamine were detected. LPS and Syn synergistically induce selective and progressive dopaminergic neurodegeneration. Microglia are functionally and morphologically activated, contributing to synergistic dopaminergic neurotoxicity elicited by LPS and Syn. NOX2-/-mice are more resistant to synergistic neurotoxicity than NOX2+/+mice in vivo and in vitro, and NOX2 inhibitor protects against synergistic neurotoxicity through decreasing microglial superoxide production, illustrating a critical role of microglial NOX2. Microglial NOX2 is activated by LPS and Syn as mRNA and protein levels of NOX2 subunits P47and gp91 are enhanced. Molecules relevant to microglial NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-КBP50as their mRNA and protein levels are elevated after treatment with LPS and Syn. Combination of exogenous and endogenous environmental factors with minimally toxic dose synergistically propagates dopaminergic neurodegeneration through activating microglial NOX2 and relevant signaling molecules, casting a new light for PD pathogenesis.
authors.affiliation: Department of Geriatrics, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. ttyyzw@163.com.|Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China. ttyyzw@163.com.|China National Clinical Research Center for Neurological Diseases, Beijing, 100050, China. ttyyzw@163.com.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing, 100069, China. ttyyzw@163.com.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China. ttyyzw@163.com.|Beijing Key Laboratory on Parkinson's Disease, Beijing, 100053, China. ttyyzw@163.com.
authors.forename: Wei
authors.identifier: 0000-0002-5239-2312
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Jun-Hua
authors.initials: JH
authors.lastname: Gao
authors.affiliation: Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Zhao-Fen
authors.initials: ZF
authors.lastname: Yan
authors.affiliation: Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Xi-Yan
authors.initials: XY
authors.lastname: Huang
authors.affiliation: Department of Geriatrics, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Geriatrics, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Zuo
authors.affiliation: Department of Geriatrics, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Shu-Yang
authors.initials: SY
authors.lastname: Yu
authors.affiliation: Department of Neurology, Beijing Tiantian Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Chen-Jie
authors.initials: CJ
authors.lastname: Cao
authors.affiliation: Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing, 100069, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China.|Beijing Key Laboratory on Parkinson's Disease, Beijing, 100053, China.|Departments of Neurobiology and Physiology, Capital Medical University, Beijing, 100069, China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000201:enzymology*; D000074662:NADPH Oxidase 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity; D021122:Protein Subunits / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051844:alpha-Synuclein / Q000633:toxicity*
chemical_list: D008070:Lipopolysaccharides; D009498:Neurotoxins; D021122:Protein Subunits; D051844:alpha-Synuclein; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2
keywords: Dopaminergic neurodegeneration; Environmental factors; Lipopolysaccharide; Microglial activation; Parkinson disease; Synergistic; α-Synuclein oligomer