Validation of small molecule targets in alpha-synuclein neurotoxicity pathways

这项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，其干扰DNA合成和翻译，并且具有作为癌症治疗剂和杀虫剂的工业用途。 第二类是β-大黄酸类似物，其具有多种性质，包括激素代谢酶的修饰、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-突触核蛋白是一种容易随着时间的推移和通过损伤在神经细胞中形成聚集体的蛋白质。 我们还将评估暴露于这些化合物后细胞生理状态的变化。 具体来说，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。 本研究结果将为该类化合物的工业应用开发提供参考。 如果这些化合物显示出强的蛋白质清除活性，它们将被进一步研究用于神经变性治疗的潜在应用。 如果这些化合物表现出很少或没有蛋白质清除活性，但在昆虫模型中显示出强大的细胞分裂抑制剂，则可以进一步研究它们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.