ABSTRACTPrions are unique, protein-only infectious agents that are responsible for a group of fatal neurodegenerativediseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle andchronic wasting disease in deer and elk. Human prion diseases are especially poorly understood, largely dueto their vast phenotypic heterogeneity that arises from a large spectrum of diverse human prion strains. It isgenerally accepted that the prion agent multiplies by binding to normal prion protein (PrPC) and converting itinto a conformationally distinct pathogenic molecule (PrPSc), but the mechanism of this process remainsunclear. A growing number of studies suggest a critical role in prion disease pathogenesis of small, relativelyprotease sensitive oligomers that appear to control two fundamental steps in the disease pathogenesis: prionreplication rate and toxicity. One of the primary objectives of the proposed research is to advance molecularlevel understanding of the properties of oligomeric PrPSc (oPrPSc) and the mechanism by which theseoligomers contribute to the pathogenic process in different phenotypes of sporadic Creutzfeldt-Jakob disease(sCJD). The first Specific Aim is to characterize the structural organization of oPrPSc and define the role of thisorganization in the replication, propagation and toxicity of the most common strains of sCJD. The second Aimis to identify early critical conformational steps in the interaction between PrPC and oPrPSc, the steps that likelyplay a major role in triggering toxic signaling, creating human prions and controlling prion evolution. Ifsuccessful, the proposed studies should not only shed new light on the pathogenic mechanism in human priondisorders, but also provide a basis for understanding the relationship between PrPSc structure and strainproperties of human prions.