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From yeast to patient neurons and back again: A powerful new discovery platform.

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Mov Disord 2014 Sep; 29(10):1231-40

Authors: Daniel F Tardiff, Vikram Khurana, Chee Yeun Chung, Susan Lindquist

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, ?-synuclein (?-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 ?-syn. The robust cellular toxicity caused by ?-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 ?-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.

PMID: 25131316 [PubMed - as supplied by publisher]

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