Conformational Engineering of Synthetic Prions

Prions are infectious proteins that can adopt self-perpetuating conformations which cause neurodegeneration. We are creating prions synthetically by refolding recombinant prion protein (PrP) into non-native conformations in solution; such synthetic prions are both pathogenic and infectious upon intracranial injection into transgenic mice. A fascinating aspect of prion disease is the existence of multiple prion strains, each of which is enciphered by a distinct conformation of the prion protein. We are engineering synthetic prions by controlling the conditions under which recombinant prion protein refolds in solution. For example, recent evidence suggests that the conformational stability of prion strains isolated from infected mice correlates directly with the incubation period observed for the onset of CNS dysfunction. In one approach, we have used conformational stability as a design parameter to guide engineering of …