Toxicant, oxidative injury, dopamine & synuclein in PD

描述（由申请人提供）：帕金森病（PD）是一种以黑质纹状体多巴胺能神经元丧失为特征的神经退行性疾病。散发性帕金森病的病因尚不清楚，尽管流行病学研究与基因环境相互作用有关。在啮齿类动物帕金森病模型的研究中，通过给药特定毒物和构建含有人类a-突触核蛋白的转基因小鼠取得了进展。毒物和a-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。胶质-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研究较少。我们假设神经元过度表达vildtype人a-synuclein触发ROS，部分由局部胶质抗氧化反应防御。随着时间的推移，这种防御机制失效，导致病理性a-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各个方面，我们设计了一种复合转基因小鼠，在神经胶质缺失谷胱甘肽过氧化物酶1 （GPX-/-）和抗氧化启动子报告子的背景下，在多巴胺能细胞（SYN+/+）中特异性过表达人类野生型a-synuclein。该复合转基因动物（SYN+/+::GPX-/-::AREhPLAP）提供了a-synuclein氧化损伤的细胞位点和神经胶质抗氧化能力受损对多巴胺能神经元功能和活力的影响。提出了三个目标。目的1。人野生型a-synuclein纯合小鼠（SYN+/+::AREhPLAP）氧化损伤的进化。目标2。SYN+/+::GPX-/-::AREhPLAP小鼠的协同损伤：多巴胺能神经元损伤加速模型。目的3在哪些细胞类型中恢复GPX- 1可减轻SYN+/+::GPX-/-::AREhPLAP小鼠的环境毒性损伤。这些研究将提供关于神经胶质抗氧化防御在a-突触核蛋白单独或与已知多巴胺能毒物联合引起的氧化损伤中的作用的清晰和可解释的数据。所得到的机制信息可能使新的胶质导向治疗方案成为可能。

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.