INTERACTIONS BETWEEN ALPHA-SYNUCLEIN/METALS/PESTICIDES

描述(摘自调查人员摘要) 拟议研究的目标是促进我们对如何 环境介质(即金属和杀虫剂)可能会与 构成蛋白质(即α-突触核蛋白)以及这种相互作用如何 导致帕金森氏病的蛋白质聚集和神经元变性。 在调查员实验室获得的初步结果表明， α-突触核蛋白的自我聚集在存在的情况下显著增强 铝或杀菌剂二乙基二硫代氨基甲酸酯(DDC)。这个 这些相互作用的潜在分子基础将在体外进行评估 为了检验α-突触核蛋白聚集增加是一种 其构象、缔合性质和 由铝或DDC引起的纤维结构。有没有可能 其他金属和杀虫剂(或药剂的组合)能够 还将测试影响α-突触核蛋白聚集率的因素 试验性的。α-突触核蛋白和α-突触核蛋白相互作用的后果 金属和杀虫剂随后将在活体动物模型中进行评估，即 酪氨酸诱导过表达人α-突触核蛋白的转基因小鼠 羟基酶启动子。因为这些小鼠表达高水平的α- 多巴胺能神经元内的突触核蛋白，它们提供了一个有价值的模型 以评估α-干扰素相互作用的病理后果 与环境因子联合的核蛋白。要检验的第一个假设是 这些动物暴露在铝或DDC(或其他金属和 农药)诱导α-突触核蛋白聚集并形成路易 体样包涵体(路易小体是 帕金森氏症)。第二个假设是， 蛋白酶体活性(细胞蛋白质降解的关键途径)发挥着重要作用。 在金属和农药诱导的路易小体形成中的作用。致信地址 这一假说，含有α-突触核蛋白的包裹体的发生 在暴露于金属和杀虫剂的过度表达的小鼠中进行监测 蛋白酶体活性的抑制物的存在。最后一个假设是 α-突触核蛋白的过度表达增加了 黑质纹状体系统对金属和农药造成的损伤。老鼠会成为 暴露于铝或DDC(或其他金属和农药)和多巴胺能 细胞损伤将在过度表达和非过度表达中进行比较 动物。这些实验的结果可能会阐明 α-突触核蛋白聚集及其在路易体形成中的作用。也许最多的 然而，重要的是，它们将促进我们对两国关系的理解 包涵体、多巴胺能变性与金属和农药之间的关系， 这两种基因都与特发性帕金森病的病因有关 疾病。

DESCRIPTION (Taken from the Investigator's Abstract) The goal of the proposed studies is to advance our understanding of how environmental agents (i.e. metals and pesticides) might interact with constitutive proteins (i.e. alpha-synuclein) and how such interactions could lead to protein aggregation and neuronal degeneration in Parkinson's Disease. Preliminary results obtained in the investigator's laboratory indicate that self-aggregation of alpha-synuclein is dramatically enhanced in the presence of either aluminum or the fungicide diethyldithiocarbamate (DDC). The underlying molecular basis of these interactions will be evaluated in vitro in order to test the hypothesis that increased alpha-synuclein aggregation is a consequence of changes in its conformation, association properties and the structure of its fibrils caused by aluminum or DDC. The possibility that other metals and pesticides (or combinations of agents) are capable of affecting the rate of alpha-synuclein aggregation will also be tested experimentally. The consequences of interactions between alpha-synuclein and metals and pesticides will then be evaluated in an in vivo animal model, i.e. transgenic mice overexpressing human alpha-synuclein under the tyrosine hydroxylase promoter. Because these mice express high levels of alpha- synuclein protein within dopaminergic neurons, they provide a valuable model in which to assess the pathologic consequences of interactions of alpha- synuclein with environmental agents. The first hypothesis to be tested in these animals is that exposure to aluminum or DDC (or other metals and pesticides) induces the aggregation of alpha-synuclein and formation of Lewy body-like inclusions (Lewy bodies are one of the pathologic hallmark of Parkinson's Disease). The second hypothesis is that an impairment of proteasome activity (a key pathway of cellular protein degradation) plays a role in metal- and pesticide-induced Lewy body-like formation. To address this hypothesis, the occurrence of alpha-synuclein-containing inclusions will be monitored in overexpressing mice exposed to metals and pesticides in the presence of inhibitors of the proteasome activity. The final hypothesis is that overexpression of alpha-synuclein increases the vulnerability of the nigrostriatal system to injury caused by metals and pesticides. Mice will be exposed to aluminum or DDC (or other metals and pesticides) and dopaminergic cell damage will be compared in overexpressing versus non-overexpressing animal. Results of these experiments are likely to clarify the mechanisms of alpha-synuclein aggregation and its role in Lewy body formation. Perhaps most importantly, however, they will further our understanding of the relationship between inclusion bodies, dopaminergic degeneration and metals and pesticides, both of which have been implicated in the etiology of idiopathic Parkinson's Disease.