Yeast Model for Studying Heritable Mammalian Prion Disease

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are infectious fatal neurodegenerative disorders that include a variety of human diseases, such as CreutzfeldtJacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru and fatal familial insomnia [1, 2]. Mammalian prion protein (PrP) in an abnormal aggregation-prone selfperpetuating (prion) conformation has been implicated as a TSE infectious agent. However, the mechanism of conversion of this protein into a prion conformation is poorly understood, thus preventing efficient development of both therapeutic interventions and prophylactic measures, targeting prion diseases. Although mutations leading to the heritable form of human prion diseases have been uncovered, primary effects triggering prion formation by mutant proteins were difficult to investigate due to the complexity of both experimental models and physiological effects of the disease. Proteins capable of producing the self-perpetuating (prion) conformations have also been identified in yeast [3, 4]. The power of yeast genetics and molecular biology has led to tremendous progress in understanding yeast prions. However, yeast prion proteins are not homologous to mammalian PrP. This prevented direct extrapolation of yeast data to mammalian and human prion diseases.