Yeast Cells as a Discovery Platform for Parkinson's Disease and other Protein Misfolding Diseases

Publisher Summary This chapter explores yeast cells as a discovery platform for Parkinson's disease (PD) and finding genetic factors and chemical compounds that modify the toxicity of proteins that are prone to misfoldings and producing toxic gain-of-function phenotypes in man. The chapter briefly reviews general features of PD and associated genes to place them in context relevant to yeast models. PD is the most common neurodegenerative movement disorder. One pathological hallmark of PD is the selective loss of the DA neurons comprising the pars compacta of the substantia nigra and the presence of proteinaceous inclusion bodies, and Lewy neurites, in the affected cells. Yeast cells also have unusually high rates of homologous recombination, and yeast has progressed from being a good model to a super model. The yeast models do not simply show nonspecific toxicity due to the accumulation of misfolded proteins. The toxicity in different models is highly specific and distinct. An advantage of yeast models in drug screening is that they have a capacity to focus compound searches on the initiating events of the diseases, particularly those involved with the misfolding and aggregation of the toxic protein. Yeast cells also provide a whole collection of technical advantages for high-throughput screening—speed, robustness, low cost, genetic manipulability—making for a compelling combination.