(504c) Synthetic Prions Shed Light on Conformational Basis of Strain Diversity

Prions are proteins which are able to adopt self-replicating conformations. In both fungi and mammals, multiple prion strains have been observed to arise from a single protein sequence, indicating that distinct protein conformations underlie prion diversity. We are generating novel prion strains synthetically, by refolding recombinant protein into different conformations in vitro and introducing these conformations into mice. We are also attempting to develop stem cell models of prion disease and to infect these with both naturally occurring and synthetic prion strains. In one major breakthrough, we have successfully produced novel synthetic prion strains that mimic rare and controversial prions occurring naturally in humans and sheep. These prion strains lack resistance to protease digestion, once believed to be an essential hallmark of mammalian prions. In other work, we have generated an array of synthetic prions with varying degrees of protease resistance. These synthetically produced prions are shedding light on the role of prion conformation in disease pathogenesis.