Protein radicals in microglia: environmental mechanisms of chronic neurotoxicity

描述(申请人提供)：帕金森氏病(PD)的病因目前尚不清楚，治疗无法阻止疾病的进展。小胶质细胞是大脑的先天免疫细胞，与帕金森病的进展有关，但驱动持续和病理激活的小胶质细胞的机制尚不清楚。环境因素与帕金森病的病因有关，可慢性激活小胶质细胞，导致多巴胺能神经元损伤。小胶质细胞的NADPH氧化酶和活性氧被认为是毒性小胶质细胞激活的关键因素，但它们如何调节小胶质细胞的功能在很大程度上还不清楚。我们的主要假设是，环境侮辱通过小胶质蛋白自由基生物化学的变化导致慢性神经炎症和随后的进行性DA神经元损伤。因此，从NF：2 p50自由基开始，我们将检验以下特定假设：百草枯、脂多糖和MPTP/MPP+可导致小胶质蛋白自由基，从而推动进行性神经炎和DA神经毒性：A)促进神经毒性促炎因子的产生(小胶质细胞启动)；B)介导小胶质细胞无法解决促炎反应。初步数据表明，小胶质细胞对促炎毒素(LPS)、直接神经毒物(MPTP/MPP+、反应性小胶质细胞增生症)和双模毒物(百草枯)的反应是通过改变其蛋白质自由基谱和增加胞浆中NF：SS p50自由基的表达来实现的。因此，从NF：SS p50自由基入手，本研究的具体目的是：1)在体外鉴定小胶质细胞蛋白自由基(NF：SS p50自由基)的促炎和启动特性；2)在体内鉴定NF：SS p50自由基在进行性DA神经元损伤中的作用；3)确定抑制NF：SS p50自由基的神经保护和抗炎作用。1我们期望首次系统地证明，核因子：生长抑素p50自由基是环境诱导的有害小胶质细胞激活的一种常见机制，从而加剧了DA的进行性神经毒性。这些研究将为帕金森病的发病机制、ROS信号转导以及环境诱导的氧化应激在神经退行性疾病中的作用定义一条新的研究途径。最后，这项工作将为识别和选择能够减缓帕金森病进展的新治疗靶点提供有价值的见解。 公共卫生相关性 这些研究将为帕金森氏病的发病机制和环境诱导的氧化应激在神经退行性疾病中的作用定义一条新的研究途径。最后，这项工作将为识别和选择能够减缓帕金森病进展的新治疗靶点提供有价值的见解。

DESCRIPTION (provided by applicant): The etiology of Parkinson's disease (PD) is currently unknown and treatment is unable to halt disease progression. Microglias, 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 have been strongly been implicated as key elements of toxic microglial activation, but how they regulate microglial function is largely unknown. Our overarching hypothesis is that environmental insult causes chronic neuroinflammation and consequent progressive DA neuron damage through changes in microglial protein radical biochemistry. Thus, beginning with the NF:2 p50 radical, we will test the specific hypothesis that paraquat, LPS, and MPTP/MPP+ cause 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 pro-inflammatory toxins (LPS), direct neurotoxicants (MPTP/MPP+, reactive microgliosis), and dual-mode toxicants (paraquat) by changing their protein radical profile and increasing expression of the cytosolic NF:ss p50 radical. Thus, beginning with the NF:ss p50 radical, the specific aims are to: 1) identify the pro-inflammatory and priming characteristics of microglial protein radicals in vitro (NF:ss p50 radical); 2) characterize the role of the NF:ss p50 radical in progressive DA neuron damage in vivo; 3) determine the neuroprotective and anti-inflammatory effect of inhibiting NF:ss p50 radical formation. 1We expect to systematically demonstrate for the first time that the NF:ss p50 radical is a common mechanism of environmentally- induced deleterious microglial activation that fuels progressive DA neurotoxicity. These studies will define a new avenue of research in PD pathogenesis, ROS-signaling, 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. PUBLIC HEALTH RELEVANCE These studies will define a new avenue of research in Parkinson's disease 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 Parkinson's disease progression.