DROSOPHILA MODELS FOR PARKINSON'S DISEASE

帕金森病果蝇模型

• 批准号: 7309728
• 负责人: Nancy M Bonini
• 金额: $ 26.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7309728
• 关键词: Drosophilidae; Lewy body; Parkinson' s disease; alpha synuclein; arthropod genetics; disease /disorder etiology; disease /disorder model; dopamine; gene environment interaction; gene mutation; genetic models; genetic screening; genetically modified animals; molecular pathology; neural degeneration; neuroprotectants; neurotoxicology; oxidative stress; phenotype; protein structure function

Many human neurodegenerative diseases are poorly understood and untreatable, including Parkinson's (PD), Alzheimer's and Huntington's diseases. For some familial forms, mutations in specific genes are known, allowing pathology to be modeled in simpler systems in order to define mechanisms and pioneer novel treatments. Toward this end, we applied the power of fly genetics to the problem of neurodegeneration by developing models for human disease in Drosophila. Here, we propose to further characterize mechanisms of alpha-synuclein (alpha-syn) associated loss of dopaminergic (DA) neuron integrity, and to study a newly-identified PD-like disorder gene, DJ-1, and its role in protection from oxidative stress. Mutations in alpha-syn are pathogenic for hereditary PD, and wild-type alpha-syn is the major protein component of the pathological aggregates called Lewy bodies that characterize sporadic PD and other synucleinopathies. In Drosophila, expression of alpha-syn compromises the integrity of DA neurons. To further investigate this, in Aim 1 we propose to generate modified forms of alpha-syn and then characterize in detail their toxicity in vivo. Modifications of interest include new hereditary mutations, truncation, and phosphorylation, which are associated with PD or have striking effects on alpha-syn fibrillization in vitro. In Aim 2, given strong links between environmental toxins and development of PD, we will expand our studies of Drosophila models to the detailed characterization of a new PD-like disorder gene, DJ-1. Preliminary studies reveal that null mutation of fly DJ-1 homologues strikingly enhances sensitivity to select oxidative toxins associated with PD, including paraquat and rotenone. Since oxidative damage is thought to be critically involved in both genetic and sporadic forms of PD, study of DJ-1 homologues will reveal new insight into these links. In Aim 3, we will apply the power of Drosophila genetics to address conserved features of alpha-syn and DJ-1-associated pathology, in order to pioneer new approaches to understand and treat human neurodegeneration.

许多人类神经退行性疾病人们知之甚少且无法治疗，包括帕金森病 (PD)、阿尔茨海默病和亨廷顿舞蹈病。对于某些家族形式，特定基因的突变是已知的，允许在更简单的系统中对病理学进行建模，以便定义机制并开拓新的治疗方法。为此，我们通过在果蝇中开发人类疾病模型，将果蝇遗传学的力量应用于神经退行性疾病问题。在这里，我们建议进一步表征与多巴胺能 (DA) 神经元完整性丧失相关的 α-突触核蛋白 (alpha-syn) 的机制，并研究新发现的 PD 样疾病基因 DJ-1 及其在保护氧化应激。 α-syn 突变是遗传性 PD 的致病因素，野生型 α-syn 是称为路易体的病理聚集体的主要蛋白质成分，路易体是散发性 PD 和其他突触核蛋白病的特征。在果蝇中，α-syn 的表达会损害 DA 神经元的完整性。为了进一步研究这一点，在目标 1 中，我们建议生成 α-syn 的修饰形式，然后详细表征其体内毒性。感兴趣的修饰包括新的遗传突变、截短和磷酸化，它们与 PD 相关或对体外 α-syn 纤维化具有显着影响。在目标 2 中，给出强链接 为了探究环境毒素与 PD 发展之间的关系，我们将把果蝇模型的研究扩展到新的 PD 样疾病基因 DJ-1 的详细表征。初步研究表明，果蝇 DJ-1 同源物的无效突变显着增强了对与 PD 相关的选择氧化毒素（包括百草枯和鱼藤酮）的敏感性。由于氧化损伤被认为与遗传性和散发性 PD 密切相关，因此对 DJ-1 同源物的研究将揭示对这些联系的新见解。在目标 3 中，我们将利用果蝇遗传学的力量来解决 α-syn 和 DJ-1 相关病理学的保守特征，以便开创理解和治疗人类神经退行性疾病的新方法。