Validation of small molecule targets in alpha-synuclein neurotoxicity pathways

这项拟议的研究旨在测试两类小分子清除果蝇神经元中蛋白质聚集的能力。一类蛋白质是拓扑异构酶抑制剂，它干扰DNA的合成和翻译，并在工业上用作癌症治疗和杀虫剂。第二类是β-甘草次酸类似物，它们具有多种性质，包括修饰激素代谢酶、抗病毒、抗细菌、抗真菌和抗原虫活性。我们将测试这些化合物清除α-突触核蛋白的能力，α-突触核蛋白是一种蛋白质，随着时间的推移和损伤，容易在神经细胞中形成聚集体。我们还将评估细胞生理状态因暴露于这些化合物而发生的变化。具体地说，我们将检测细胞存活和细胞形态的变化，这是细胞健康的读数。本研究的结果将为这类化合物的工业化应用提供参考。如果这些化合物显示出很强的蛋白质清除活性，它们将被进一步研究，因为它们可能应用于神经退行性变治疗。如果这些化合物在昆虫模型中表现出很少或根本没有蛋白质清除活性，但却显示出强大的细胞分裂抑制作用，它们可能会被进一步研究，作为杀虫剂的潜在用途。

The proposed research aims to test the capacity of two classes of small molecules to clear aggregation of proteins in the neurons of the fruitfly, Drosophila melanogaster. One class of proteins are topoisomerase inhibitors, which interfere with DNA synthesis and translation, and have industrial use as cancer therapeutics and pesticides. The second class are beta-glycyrrhetinic acid analogs, which have multiple properties including modification of hormonal metabolic enzymes, antiviral, antibacterial, antifungal, and antiprotozoal activities. We will test the capacity of these compounds to clear alpha-synuclein, a protein that is susceptible to forming aggregates in neural cells over time and through injury. We will also assess the changes in cellular physiological status in response to exposure to these compounds. Specifically, we will detect changes in cell survival as well as cell morphology, which is a readout of cellular health. The outcome of this research will be informative for the development of industrial application of these compounds. If the compounds show strong protein clearance activity, they will be studied further for their potential application to neurodegeneration therapeutics. If the compounds demonstrate little or no protein clearance activity, yet show powerful suppressors of cell division in the insect model, they may be studied further for their potential use as pesticides.