Abstract
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.
Highlights
Parkinson’s disease (PD) is the second most common neurological disorder and the most common movement disorder
Our approach engages an application of small volume tubes requiring as little as 0.5 ml fly food that may be supplemented with small molecule compounds
We tested the FlyTracker system on a well-described fly model of sporadic PD to demonstrate its power as a sensitive method for investigation of the in vivo effects of small molecules, previously reported to modulate aS aggregation in vitro
Summary
Parkinson’s disease (PD) is the second most common neurological disorder and the most common movement disorder. It is characterized by widespread degeneration of subcortical structures of the brain, especially dopaminergic neurons in the substantia nigra. These changes are coupled with bradykinesia (slowness in execution and decrease of amplitude and range of movements), rigidity and tremor, resulting in difficulties in walking and abnormal gait in patients [1]. Small-molecule effects on Drosophila model of Parkinson’s design, data collection and analysis, decision to publish, or preparation of the manuscript The assembly process of the intrinsically-unstructured protein α-synuclein (aS) has been linked to the molecular basis of PD. aS is a major component of the amyloid
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