title: From yeast to patient neurons and back again: powerful new discovery platform.
abstract: 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.
authors.affiliation: Whitehead Institute for Biomedical Research (WIBR), Cambridge, Massachusetts, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Tardiff
authors.forename: Vikram
authors.initials: V
authors.lastname: Khurana
authors.forename: Chee Yeun
authors.initials: CY
authors.lastname: Chung
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D006801:Humans; D009069:Movement Disorders / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D057170:Translational Research, Biomedical; D015003:Yeasts / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein
keywords: Parkinson's disease; drug target identification; human iPS cells; phenotypic screen; yeast; α−synuclein