Parkinson's disease (PD) patients have excessive iron depositions in substantia nigra (SN). Neuroinflammation characterized by microglial activation is pivotal for dopaminergic neurodegeneration in PD. However, the role and mechanism of microglial activation in iron-induced dopaminergic neurodegeneration in SN remain unclear yet. This study aimed to investigate the role and mechanism of microglial beta-nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) activation in iron-induced selective and progressive dopaminergic neurodegeneration. Multiple primary midbrain cultures from rat, NOX2(+/+) and NOX2(-/-) mice were used. Dopaminergic neurons, total neurons, and microglia were visualized by immunostainings. Cell viability was measured by MTT assay. Superoxide (O-2(center dot-)) and intracellular reactive oxygen species (iROS) were determined by measuring SOD-inhibitable reduction of tetrazolium salt WST-1 and DCFH-DA assay. mRNA and protein were detected by real-time PCR and Western blot. Iron induces selective and progressive dopaminergic neurotoxicity in rat neuron-microglia-astroglia cultures and microglial activation potentiates the neurotoxicity. Activated microglia produce a magnitude of O-2(center dot-) and iROS, and display morphological alteration. NOX2 inhibitor diphenylene iodonium protects against iron-elicited dopaminergic neurotoxicity through decreasing microglial O-2(center dot-) generation, and NOX2(-/-) mice are resistant to the neurotoxicity by reducing microglial O-2(center dot-) production, indicating that iron-elicited dopaminergic neurotoxicity is dependent of NOX2, a O-2(center dot-)-generating enzyme. NOX2 activation is indicated by the increased mRNA and protein levels of subunits P47 and gp91. Molecules relevant to NOX2 activation include PKC-sigma, P38, ERK1/2, JNK, and NF-KBP65 as their mRNA and protein levels are enhanced by NOX2 activation. Iron causes selective and progressive dopaminergic neurodegeneration, and microglial NOX2 activation potentiates the neurotoxicity. PKC-sigma, P38, ERK1/2, JNK, and NF-KBP65 are the potential molecules relevant to microglial NOX2 activation.
基金：
National Basic Research Program of ChinaNational Basic Research Program of China [2011CB504100]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81071015, 30770745, 81030062]; Natural Science Foundation of Beijing, ChinaBeijing Natural Science Foundation [7082032]; High Level Technical Personnel Training Project of Beijing Health System, China [2009-3-26]; Excel lent Personnel Training Project of Beijing, China [20071D0300400076]; Capital Clinical Characteristic Application Research Project [Z121107001012161]; Important National Science and Technology Specific Project [2011ZX09102-003-01]; Beijing Natural Science FoundationBeijing Natural Science Foundation [kz200910025001]; Basic-Clinical Research Cooperation Funding of Capital Medical University [10JL49]
第一作者机构：[1]Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol, Beijing 100050, Peoples R China;[2]Beijing Inst Brain Disorders, Parkinsons Dis Ctr, Beijing 100053, Peoples R China;[3]Beijing Key Lab Parkinsons Dis, Beijing 100053, Peoples R China;
通讯作者：
通讯机构：[1]Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol, Beijing 100050, Peoples R China;[2]Beijing Inst Brain Disorders, Parkinsons Dis Ctr, Beijing 100053, Peoples R China;[3]Beijing Key Lab Parkinsons Dis, Beijing 100053, Peoples R China;
推荐引用方式(GB/T 7714)：
Zhang Wei,Yan Zhao-fen,Gao Jun-hua,et al.Role and Mechanism of Microglial Activation in Iron-Induced Selective and Progressive Dopaminergic Neurodegeneration[J].MOLECULAR NEUROBIOLOGY.2014,49(3):1153-1165.doi:10.1007/s12035-013-8586-4.
APA：
Zhang, Wei,Yan, Zhao-fen,Gao, Jun-hua,Sun, Li,Huang, Xi-yan...&Wang, Xiao-min.(2014).Role and Mechanism of Microglial Activation in Iron-Induced Selective and Progressive Dopaminergic Neurodegeneration.MOLECULAR NEUROBIOLOGY,49,(3)
MLA：
Zhang, Wei,et al."Role and Mechanism of Microglial Activation in Iron-Induced Selective and Progressive Dopaminergic Neurodegeneration".MOLECULAR NEUROBIOLOGY 49..3(2014):1153-1165
