Molecular mechanisms encoding quantitative and qualitative traits of prion strains

Abstract

Yeast, fungal, and mammalian prions determine heritable as well as infectious traits. In mammals, prions cause a group of fatal and rapidly progressive neurodegenerative diseases, originally described as transmissible spongiform encephalopathies (TSEs). Variations in prions, which cause different disease phenotypes, are referred to as strains. Mammalian prion strains are differentiated by qualitative characteristics such as clinical symptoms, brain pathology, targeted brain anatomical areas and cells, or Western blot patterns of glycosylated or deglycosylated pathogenic prion protein (PrPSc). Quantitative prion traits are determined by incubation time, prion dose response, proteolytic sensitivity, and conformational stability of PrPSc. The high degree of fidelity with which prion strains replicate requires a precise molecular mechanism that can account for all these characteristics. Remarkable progress in the past decade produced many lines of evidence arguing that prion traits are encoded in the self-replicating conformation of PrPSc that is unique for each strain. Thus, prions behave like proteinaceous genes. The determination of the full spectrum of human and animal prion strains and the conformational features in the pathogenic human prion protein that govern replication of prion strains is essential for the development of diagnostic as well as therapeutic strategies.