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 amyloid conformations in vitro and introducing these conformations into mice. 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 by engineering the conformational stability of the amyloid inoculated into the mice. The resulting synthetic prions have properties that correlate to some features of the amyloid used to generate them. These synthetically produced prions are shedding light on the role of prion conformation in disease pathogenesis.

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