Using Yeast to Search for Drugs to Target Alpha-Synuclein in Parkinson's Disease

Misfolded forms of alpha-synuclein have been identified as a proximate cause of dying brain cells in Parkinson's disease (PD), and so there is considerable interest in ways to remove this protein or block its mode of action. The research reported here is a good example of the platforms that researchers build in order to search for compounds that might be developed into drugs for this sort of task. Even when a specific protein or mechanism has been identified, at the present time it isn't yet possible to step directly to the answer and design the right molecule for the job. It remains more efficient to explore tens of thousands of candidates in the lab.

In the search for compounds that might alter a protein's behavior or function - such as that of alpha-synuclein - drug companies often rely on so-called target-based screens that test the effect large numbers of compounds have on the protein in question in rapid, automated fashion. Though efficient, such an approach is limited by the fact that it essentially occurs in a test tube. Seemingly promising compounds emerging from a target-based screen may act quite differently when they're moved from the in vitro environment into a living setting.

To overcome this limitation [researchers have] turned to phenotypic screens in which candidate compounds are studied within a living system. Yeast cells - which share the core cell biology of human cells - serve as living test tubes in which to study the problem of protein misfolding and to identify possible solutions. Yeast cells genetically modified to overproduce alpha-synuclein serve as robust models for the toxicity of this protein that underlies PD.

In a screen of nearly 200,000 compounds, [researchers] identified one chemical entity that not only reversed alpha-synuclein toxicity in yeast cells, but also partially rescued neurons in the model nematode C. elegans and in rat neurons. Significantly, cellular pathologies including impaired cellular trafficking and an increase in oxidative stress, were reduced by treatment with the identified compound. [Researchers then examined] neurons derived from induced pluripotent stem (iPS) cells generated from Parkinson's patients. The cells and differentiated neurons (of a type damaged by the disease) were derived from patients that carried alpha-synuclein mutations and develop aggressive forms of the disease. [The researchers] used the wealth of data from the yeast alpha-synuclein toxicity model to clue them in on key cellular processes that became perturbed as patient neurons aged in the dish. Strikingly, exposure to the compound identified via yeast screens [reversed] the damage in these neurons.

Link: http://wi.mit.edu/news/archive/2013/yeast-human-stem-cells-drive-discovery-new-parkinson-s-disease-drug-targets

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