title: P2X7 receptor is critical in α-synuclein--mediated microglial NADPH oxidase activation.
abstract: Activated microglia are commonly observed in individuals with neurodegenerative disorders, including Parkinson's disease (PD) and are believed to contribute to neuronal death. This process occurs at least due partially to nicotinamide adenine dinucleotide phosphate oxidase (PHOX) activation, which leads to the production of superoxide and oxidative stress. α-Synuclein (α-Syn), a key protein implicated in PD pathogenesis, can activate microglia, contributing to death of dopaminergic neurons. Here, microglial cells (BV2) and primary cultured microglia were used to study the role that the purinergic receptor P2X7 plays in recognizing α-Syn and promoting PHOX activation. We demonstrate that both wild type and A53T mutant α-Syn readily activate PHOX, with the A53T form producing more rapid and sustained effects,that is, oxidative stress and cellular injuries. Furthermore, this process involves the activation of phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway. Thus, it is concluded that stimulation of the microglial P2X7 receptor by extracellular α-Syn, with PI3K/AKT activation and increased oxidative stress, could be an important mechanism and a potential therapeutic target for PD.
authors.affiliation: Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Tianfang
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Hoekstra
authors.affiliation: Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Heng
authors.affiliation: Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurology, Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Science and Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: chen_sd@medmail.com.cn.
authors.forename: Shengdi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA; Department of Pathology, Peking University Third Hospital/Institute of Basic Science, Peking University Health Science Center, Beijing, China. Electronic address: zhangpresent@gmail.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology*; D058990:Molecular Targeted Therapy; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; D058486:Receptors, Purinergic P2X7; D051844:alpha-Synuclein; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Microglia; P2X7 receptor; PI3K/AKT signaling; Parkinson's disease; α-Synuclein