Pokrzywa Małgorzata, Pawełek Katarzyna, Kucia Weronika Elżbieta, Sarbak Szymon, Chorell Erik, Almqvist Fredrik, Wittung-Stafshede Pernilla
Airoptic Sp. z o.o., Poznań, Poland.
Department of Chemistry, Umeå University, Umeå, Sweden.
PLoS One. 2017 Sep 1;12(9):e0184117. doi: 10.1371/journal.pone.0184117. eCollection 2017.
Alpha-synuclein (aS) amyloid formation is involved in Parkinson's disease (PD); therefore, small molecules that target aS and affect its aggregation are of interest as future drug candidates. We recently reported modified ring-fused 2-pyridones that modulate aS amyloid formation in vitro. Here, we describe the effects of such molecules on behavioral parameters of a Drosophila model of PD (i.e., flies expressing human aS), using a new approach (implemented in a commercially available FlyTracker system) to quantify fly mobility. FlyTracker allows for automated analysis of walking and climbing locomotor behavior, as it collects large sequences of data over time in an unbiased manner. We found that the molecules per se have no toxic or kinetic effects on normal flies. Feeding aS-expressing flies with the amyloid-promoting molecule FN075, remarkably, resulted in increased fly mobility at early time points; however, this effect switched to reduced mobility at later time points, and flies had shorter life spans than controls. In contrast, an amyloid inhibitor increased both fly kinetics and life span. In agreement with increased aS amyloid formation, the FN075-fed flies had less soluble aS, and in vitro aS-FN075 interactions stimulated aS amyloid formation. In addition to a new quantitative approach to probe mobility (available in FlyTracker), our results imply that aS regulates brain activity such that initial removal (here, by FN075-triggered assembly of aS) allows for increased fly mobility.
α-突触核蛋白（aS）淀粉样蛋白的形成与帕金森病（PD）有关；因此，靶向aS并影响其聚集的小分子作为未来的候选药物备受关注。我们最近报道了修饰的稠环2-吡啶酮，它们在体外可调节aS淀粉样蛋白的形成。在此，我们使用一种新方法（在市售的FlyTracker系统中实现）来量化果蝇的运动能力，描述了这类分子对PD果蝇模型（即表达人aS的果蝇）行为参数的影响。FlyTracker能够自动分析行走和攀爬运动行为，因为它能随着时间以无偏差的方式收集大量数据序列。我们发现这些分子本身对正常果蝇没有毒性或动力学影响。值得注意的是，用促进淀粉样蛋白形成的分子FN075喂养表达aS的果蝇，在早期时间点会导致果蝇运动能力增强；然而，这种效果在后期时间点转变为运动能力下降，且果蝇的寿命比对照组短。相比之下，一种淀粉样蛋白抑制剂可提高果蝇的运动能力和寿命。与aS淀粉样蛋白形成增加一致，用FN075喂养的果蝇中可溶性aS较少，并且体外aS与FN075的相互作用会刺激aS淀粉样蛋白的形成。除了一种用于探测运动能力的新定量方法（FlyTracker中可用）外，我们的结果表明aS调节大脑活动，使得最初的清除（在此处，通过FN075触发的aS组装）能提高果蝇的运动能力。
