Protein radicals in microglia: environmental mechanisms of chronic neurotoxicity

帕金森氏病(PD)的病因目前尚不清楚，治疗无法停止 疾病的发展。小胶质细胞是大脑的先天免疫细胞，与帕金森病有关 进展，但驱动持续和病理激活的小胶质细胞的机制是 人们对此知之甚少。环境因素与帕金森病的病因有关，并可慢性 激活小胶质细胞，造成多巴胺能神经元损伤。小胶质细胞NADPH氧化酶和 活性氧可能在有害的小胶质细胞激活中起作用，但它们如何 对小胶质细胞功能的调节在很大程度上是未知的。我们最重要的假设是 环境伤害(MPTP/MPP+和内毒素)会导致慢性神经炎和 小胶质细胞蛋白自由基生化改变对DA神经元的进行性损伤。 从核因子κβ自由基开始，我们将检验内毒素和mptp/mpp+- 诱导的NADPH氧化酶激活引起小胶质细胞蛋白自由基，推动进展 神经炎症和DA的神经毒性：a)增加神经毒性前体的产生 炎症因子(小胶质细胞启动)；B)介导小胶质细胞不能分解亲本。 炎症反应。初步数据表明，小胶质细胞对MPP+诱导的DA有反应 神经元损伤信号和内毒素通过改变其蛋白质自由基谱和增加 胞内核因子κβp50自由基。因此，从NFκβ自由基开始，具体目标是：1) NADPH氧化酶衍生蛋白的促炎和启动特性鉴定 自由基(NFκβp50自由基)；2)星形胶质细胞-小胶质细胞相互作用在NFκβp50中的作用 自由基形成、神经炎症和小胶质细胞介导的DA神经毒性；3)表征 NADPH-氧化酶衍生的NF-κβp50自由基在进行性DA神经元损伤中的作用 4)测定抑制核因子κβp50的神经保护和抗炎作用 部首的形成和作用。我们希望首次系统地展示 环境的侮辱导致小胶质细胞中的蛋白质自由基，从而助长了进行性DA 神经毒性，并确定这些有害的小胶质细胞激活的标志物(即，核因子κβp50)。 这些研究将为帕金森病发病机制的研究开辟一条新的途径，并探讨其在帕金森病发病机制中的作用。 神经退行性疾病中环境诱导的氧化应激。最后，这项工作将 为新疗法的确定和时机选择提供有价值的见解 能够减缓帕金森病进展的目标。

The etiology of Parkinson’s disease (PD) is currently unknown and treatment is unable to halt disease progression. Microglia, the innate immune cells of the brain, are implicated in PD progression, but the mechanisms driving continuous and pathologically activated microglia are poorly understood. Environmental factors are associated with PD etiology and can chronically activate microglia to cause dopaminergic (DA)neuron damage. Microglial NADPH oxidase and reactive oxygen species may have a role in deleterious microglial activation, but how they regulate microglial function is largely unknown. Our overarching hypothesis is that environmental insult (MPTP/MPP+ and LPS) causes chronic neuroinflammation and progressive DA neuron damage through changes in microglial protein radical biochemistry. Beginning with the NFκβ radical, we will test the specific hypothesis that LPS and MPTP/MPP+- induced NADPH oxidase activation causes microglial protein radicals that drive progressive neuroinflammation and DA neurotoxicity by: A) enhancing the production of neurotoxic pro- inflammatory factors (microglial priming); B) mediating the failure of microglia to resolve the pro- inflammatory response. Preliminary data indicate that microglia respond to MPP+-induced DA neuron-injury signals and LPS by changing their protein radical profile and increasing the cytosolic NFκβ p50 radical. Thus, beginning with the NFκβ radical, the specific aims are to: 1) identify the proinflammatory and priming characteristics of NADPH oxidase-derived protein radicals (NFκβ p50 radical); 2) define the role of astrocyte-microglia interactions on NFκβ p50 radical formation, neuroinflammation, and microglia-mediated DA neurotoxicity; 3) characterize the role of the NADPH-oxidase derived NFκβ p50 radical in progressive DA neuron damage in vivo; 4) determine the neuroprotective and anti-inflammatory effect of inhibiting NFκβ p50 radical formation and function. We expect to systematically demonstrate for the first time that environmental insult causes protein radicals in microglia that fuel progressive DA neurotoxicity and identify these markers of deleterious microglial activation (i.e. NFκβ p50). These studies will define a new avenue of research in PD pathogenesis and the role of environmentally-induced oxidative stress in neurodegenerative disease. Finally, this work will provide valuable insight into the identification and timing of novel therapeutic targets capable of slowing PD progression.