DROSOPHILA MODELS FOR PARKINSON'S DISEASE

许多人类神经退行性疾病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病。对于某些家族性形式，已知特定基因的突变，允许在更简单的系统中对病理进行建模，以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变性问题。在这里，我们建议进一步表征α-突触核蛋白（α-syn）相关的多巴胺（DA）神经元完整性丧失的机制，并研究一个新发现的PD样疾病基因，DJ-1，及其在保护氧化应激中的作用。 α-syn的突变是遗传性PD的致病性，野生型α-syn是称为路易体的病理聚集体的主要蛋白质组分，其表征散发性PD和其他突触核蛋白病。在果蝇中，α-syn的表达损害了DA神经元的完整性。为了进一步研究这一点，在目标1中，我们提出产生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，这些与PD相关或对体外α-合成纤维化具有显著影响。在目标2中，考虑到 环境毒素和PD的发展之间的关系，我们将扩大我们的研究果蝇模型的详细特征的一个新的PD样疾病基因，DJ-1。初步研究表明，果蝇DJ-1同源物的无效突变显著增强了对与PD相关的氧化毒素（包括百草枯和鱼藤酮）的敏感性。由于氧化损伤被认为是关键参与遗传和散发形式的PD，DJ-1同源物的研究将揭示这些联系的新见解。在目标3中，我们将应用果蝇遗传学的力量来解决alpha-syn和DJ-1相关病理学的保守特征，以开拓新的方法来理解和治疗人类神经变性。

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.