Yeast cells as a discovery platform for neurodegenerative disease

Protein conformational changes govern most processes in cell biology. Because these phenomena are universal, we use a variety of model systems to study them, from yeast to mice. Recently we've been particularly interested in proteins that undergo self-perpetuating changes in conformation, such as prions. Surprisingly, our studies in yeast suggested that a cytoplasmic form of the mammalian prion, PrP, might be involved in disease. Mouse models we constructed to test this possibility established that cytoplasmic PrP is sufficient to cause neurodegenerative disease. This led us to establishing other models of protein-folding diseases in yeast, with the aim of learning about the causes of misfolding, the nature of its cyto-toxic effects, and mechanisms that might ameliorate them. A variety of high throughput methods are being used to exploit these. Computational methods are being employed to integrate data from different platforms. Results with alpha synuclein (whose misfolding is directly related to Parkinson's disease) and Huntingtin (whose misfolding is directly related to Huntingtin's disease) will be discussed.