DISSECTING THE MECHANISM OF PRION FORMATION WITH A PERMISSIVE HOST

Project SummaryPrion diseases are infectious neurodegenerative diseases caused by the inducedconformational change of a host-encoded glycoprotein, PrPC, into a pathogenicconformer, PrPSc. Currently, there are no vaccines or therapies available for theseinvariably fatal diseases, primarily because we do not understand the mechanism ofPrPSc formation.Interestingly, there are large differences in host susceptibility to prion infection betweendifferent animal species. For instance, rabbits appear to be resistant to all prion strains,while bank voles appear to be a universal host. This variation, which is dependent onPrP sequence, provides us with a unique opportunity to identify the key steps in PrPScformation shared by all species. Using rigorous biochemical tools developed in ourlaboratory, we will exploit these naturally occurring differences in host susceptibility todissect the mechanism of prion replication. Specifically, this powerful comparativebiochemistry approach will be used to accomplish the following aims:1. Directly test the protein-only hypothesis of prion infectivity.2. Identify and characterize PrPC domains that control susceptibility to prion conversion.3. Determine whether cofactor molecules and post-translational modifications restrictthe host range of prion infection.The results of this project will greatly advance our understanding of the prion replicationmechanism. They will also impact our understanding of related, prion-like diseases,such as Alzheimer's and Parkinson's disease.