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Mov Disord. 2014 Sep;29(10):1231-40. doi: 10.1002/mds.25989. Epub 2014 Aug 14.

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

Author information

1
Whitehead Institute for Biomedical Research (WIBR), Cambridge, Massachusetts, USA.

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.

KEYWORDS:

Parkinson's disease; drug target identification; human iPS cells; phenotypic screen; yeast; α−synuclein

PMID:
25131316
DOI:
10.1002/mds.25989
[Indexed for MEDLINE]

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