Toxicant, oxidative injury, dopamine & synuclein in PD

有毒、氧化损伤、多巴胺

• 批准号: 7196862
• 负责人: Kathleen Anne Maguire-Zeiss
• 金额: $ 5.76万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-08 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196862
• 关键词: Address; Aging; Alkaline Phosphatase; Animals; Antibodies; Antioxidants; Astrocytes; Bioenergetics; Biological Assay; Birefringence; Bradykinesia; Brain; Cell Death; Cells; Cessation of life; Classification; Clinical; Cogwheel Rigidity; Congo Red; Corpus striatum structure; Coupled; Cytoplasmic Inclusion; Data; Defect; Defense Mechanisms; Disease; Disease model; Dissection; Dopamine; Dopaminergic Cell; Elements; Engineering; Epidemiologic Studies; Etiology; Evolution; Exhibits; Exposure to; Face; Facility Construction Funding Category; Freezing; Gene Dosage; Generations; Genes; Genetic; Genotype; Human; Immunohistochemistry; In Situ Hybridization; Inherited; Injection of therapeutic agent; Injury; Laboratories; Lewy Bodies; Lipids; Measurement; Measures; Mediating; Messenger RNA; Metabolism; Microglia; Midbrain structure; Modeling; Mus; Neurites; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Oxidants; Oxidative Stress; Paraquat; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pattern; Placenta; Play; Principal Investigator; Protein Overexpression; Proteins; Quinones; Reactive Oxygen Species; Relative (related person); Reporter; Reporter Genes; Reporting; Response Elements; Rest Tremor; Rodent; Role; Rotenone; Saline; Serotyping; Substantia nigra structure; Testing; Therapeutic; Time; TimeLine; Toxic Environmental Substances; Toxicant exposure; Transgenes; Transgenic Animals; Transgenic Mice; Tyrosine 3-Monooxygenase; Virus; Week; Western Blotting; aged; base; benzoquinone; cell type; cohort; conformer; density; dopamine quinone; dopamine transporter; dopaminergic neuron; gene environment interaction; glutathione peroxidase; immunocytochemistry; loss of function; neuronal cell body; novel; oxidation; presynaptic; programs; promoter; research study; response; restoration; synuclein; toxicant; vector; vector control

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 wildtype 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. 3 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-1mitigate 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.

描述（由申请人提供）：帕金森病（PD）是一种神经退行性疾病，其特征在于黑质纹状体多巴胺能神经元的丧失。尽管流行病学研究表明与基因环境相互作用有关，但散发性帕金森病的病因仍不清楚。通过施用特定毒物和构建含有人α-突触核蛋白的转基因小鼠，啮齿类动物帕金森病模型取得了进展。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。神经胶质-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尚不清楚。我们假设野生型人α-突触核蛋白的神经元过度表达会触发ROS，而ROS在一定程度上受到局部胶质细胞抗氧化反应的保护。随着时间的推移，这种防御机制失效，导致病理性α-突触核蛋白错误折叠、突触前多巴胺神经元损伤并最终导致细胞死亡。为了测试这一假设的各个方面，我们设计了一种复合转基因小鼠，在胶质细胞耗尽的谷胱甘肽过氧化物酶 1 (GPX-/-) 和抗氧化启动子报告基因的背景下，在多巴胺能细胞 (SYN+/+) 中特异性过表达人类野生型 α-突触核蛋白。这种复合转基因动物（SYN+/+::GPX-/-::AREhPLAP）可用于研究α-突触核蛋白造成的氧化损伤的细胞位点以及神经胶质细胞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3个目标。目标 1. 人类野生型 a-突触核蛋白纯合小鼠 (SYN+/+::AREhPLAP) 氧化损伤的演变。目标 2. SYN+/+::GPX-/-::AREhPLAP 小鼠的协同损伤：加速多巴胺能神经元损害的模型。目标 3 在 SYN+/+::GPX-/-::AREhPLAP 小鼠中，Gpx-1 的恢复可减轻环境毒物损伤。这些研究将产生关于神经胶质细胞抗氧化防御在单独的α-突触核蛋白以及与已知的多巴胺能毒物组合引起的氧化损伤中的作用的清晰且可解释的数据。所获得的机制信息可能会促成新的以神经胶质为导向的治疗方案。