Infectious and pathogenic forms of PrP

Abstract

Prion diseases are transmitted by unconventional infectious agents (prions) generated by the conformational conversion of PrP C, a normal, cell-surface glycoprotein, into PrP Sc, a misfolded isoform that propagates itself by a self-templating mechanism. Although PrP Sc has commonly been considered the primary neurotoxic species in prion diseases, strong experimental evidence now challenges this dogma and suggests that alternative pathogenic forms of PrP may operate by altering the normal physiological function of PrP C. In the past 15 years, we and others have generated cellular and animal models for studying prion diseases that shed light on important aspects of PrP infectivity, aggregation, and toxicity. In this chapter, we review some of these results and discuss our current understanding of the molecular processes responsible for the formation of aberrant forms of PrP and their acquisition of infectious and toxic properties.