Toxicant, oxidative injury, dopamine & synuclein in PD

描述(申请人提供)：帕金森病(PD)是一种以黑质纹状体多巴胺能神经元丢失为特征的神经退行性疾病。虽然流行病学研究表明与基因环境的相互作用有关，但散发性帕金森病的病因尚不清楚。通过给予特定的毒物和构建携带人α-突触核蛋白的转基因小鼠，在啮齿动物帕金森病模型方面取得了进展。毒物和α-突触核蛋白之间的致病联系似乎在于它们产生氧化损伤的独特能力。较少被研究的是神经胶质细胞-神经元相互作用促进腹侧中脑多巴胺神经元氧化损伤和死亡的作用。我们假设神经元过度表达人类α-突触核蛋白，触发部分由局部神经胶质抗氧化反应保护的ROS。随着时间的推移，这种防御机制失效，导致病理性的α-突触核蛋白错误折叠，突触前多巴胺神经元损伤，最终导致细胞死亡。为了验证这一假设的每一个方面，我们设计了一个复合转基因小鼠，在胶质细胞耗竭谷胱甘肽过氧化物酶1(GPX-/-)和抗氧化剂启动子-报告基因的背景下，在多巴胺能细胞(SYN/)中特异性地过表达人类野生型a-突触核蛋白。这种复合转基因动物(SYN/：：GPX-/-：：AREhPLAP)为研究α-突触核蛋白引起的氧化损伤及其细胞部位，以及胶质细胞抗氧化能力受损对多巴胺能神经元功能和存活的影响提供了基础。提出了三个目标。目的1.人野生型α-突触核蛋白纯合子小鼠(SYN/：：AREhPLAP)氧化损伤的演变。目的2.SYN/：：GPX-/-：AREhPLAP小鼠的协同损伤：一种加速的多巴胺能神经元损伤模型。目的3恢复Gpx-1的哪种细胞类型可以减轻SYN/：：GPx-/-：AREhPLAP小鼠的环境毒物损伤。这些研究将产生清晰和可解释的数据，说明胶质细胞抗氧化防御在α-突触核蛋白单独和与已知的多巴胺能毒剂联合诱导的氧化损伤中的作用。获得的机制信息可能使新的面向神经胶质的治疗计划成为可能。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of nigrostriatal dopaminergic neurons. The etiology of sporadic Parkinson's disease remains unknown although epidemiologic studies implicate to gene environment interaction. Progress in Parkinson's disease modeling in rodents has been achieved by administration of specific toxicants and through construction of transgenic mice harboring human a-synuclein. The pathogenic linkage between toxicant and a-synuclein appears to lie in their unique capacities to produce oxidative injury. Less well investigated is role of glial-neuronal interactions promoting oxidative damage and death of ventral midbrain dopamine neurons. We hypothesize that neuronal overexpression of \vildtype human a-synuclein triggers ROS that are, in part, defended by local glial anti-oxidant responses. Over time this defense mechanism fails resulting in pathologic a-synuclein misfolding, presynaptic dopamine neuron injury and ultimately cell death. To test each facet of this hypothesis, we engineered a compound transgenic mouse to specifically overexpress human wild type a-synuclein in dopaminergic cells (SYN+/+) on the background of glial depleted glutathione peroxidase 1 (GPX-/-) and an antioxidant promoter-reporter. This compound transgenic animal (SYN+/+::GPX-/-::AREhPLAP) affords the study of and cellular locus of oxidative injury wrought by a-synuclein and the impact of impaired glial anti-oxidant capacity on dopaminergic neuron function and viability. Three Aims have been proposed. Aim 1. The evolution of oxidant injury in human wild type a-synuclein homozygous mice (SYN+/+::AREhPLAP). Aim 2. Synergistic injury in SYN+/+::GPX-/-::AREhPLAP mice: a model of accelerated dopaminergic neuron compromise. Aim 3 In which cell types does restoration ofGpx-1 mitigate environmental toxicant injury in SYN+/+::GPX-/-::AREhPLAP mice. These studies will produce clear and interpretable data concerning the role of glia anti-oxidant defense in oxidative injury elicited by a-synuclein alone and in combination with a known dopaminergic toxicant. The mechanistic information derived may enable new glial-oriented therapeutic initiatives.