Validation of small molecule targets in alpha-synuclein neurotoxicity pathways

点击翻译按钮获取中文摘要

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.