From yeast to patient neurons and back again: Powerful new discovery platforms

No disease‐modifying therapies are available for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). The lack of therapies has been impeded by a paucity of validated drug targets and problematic cell‐based model systems. New approaches are therefore needed to identify genes and compounds that directly target the underlying cellular pathologies elicited by the pathological protein, α−synuclein (α−syn). This small, lipid‐binding protein impinges on evolutionarily conserved processes such as vesicle trafficking and mitochondrial function. For decades, the genetically tractable, single‐cell eukaryote, budding yeast, has been used to study nearly all aspects of cell biology. More recently, yeast has revealed key insights into the underlying cellular pathologies caused by α−syn. The robust cellular toxicity caused by α−syn expression facilitates unbiased high‐throughput small‐molecule screening. Critically, one must validate the discoveries made in yeast in disease‐relevant neuronal models. Here, we describe two recent reports that together establish yeast‐to‐human discovery platforms for synucleinopathies. In this exemplar, genes and small molecules identified in yeast were validated in patient‐derived neurons that present the same cellular phenotypes initially discovered in yeast. On validation, we returned to yeast, where unparalleled genetic approaches facilitated the elucidation of a small molecule's mode of action. This approach enabled the identification and neuronal validation of a previously unknown “druggable” node that interfaces with the underlying, precipitating pathologies caused by α−syn. Such platforms can provide sorely needed leads and fresh ideas for disease‐modifying therapy for these devastating diseases. © 2014 International Parkinson and Movement Disorder Society