Probing the role of structural features of mouse PrP in yeast by expression as Sup35-PrP fusions

Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, UK.
Prion (Impact Factor: 2.24). 07/2012; 6(3):201-10. DOI: 10.4161/pri.19214
Source: PubMed


The yeast Saccharomyces cerevisiae is a tractable model organism in which both to explore the molecular mechanisms underlying the generation of disease-associated protein misfolding and to map the cellular responses to potentially toxic misfolded proteins. Specific targets have included proteins which in certain disease states form amyloids and lead to neurodegeneration. Such studies are greatly facilitated by the extensive 'toolbox' available to the yeast researcher that provides a range of cell engineering options. Consequently, a number of assays at the cell and molecular level have been set up to report on specific protein misfolding events associated with endogenous or heterologous proteins. One major target is the mammalian prion protein PrP because we know little about what specific sequence and/or structural feature(s) of PrP are important for its conversion to the infectious prion form, PrP (Sc) . Here, using a study of the expression in yeast of fusion proteins comprising the yeast prion protein Sup35 fused to various regions of mouse PrP protein, we show how PrP sequences can direct the formation of non-transmissible amyloids and focus in particular on the role of the mouse octarepeat region. Through this study we illustrate the benefits and limitations of yeast-based models for protein misfolding disorders.

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    • "For instance in Creutzfeld-Jakob disease, PrPSc accumulation results in neuronal loss causing rapid progressive dementia and cerebellar dysfunction (Imran and Mahmood, 2011). Yeast models have been established expressing mammalian PrPC (Li and Harris, 2005; Bounhar et al., 2006; Halfmann et al., 2010; Josse et al., 2012). PrPC expression was not cytotoxic for yeast cells (Li and Harris, 2005; Bounhar et al., 2006). "
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