A New Mechanism for Transmissible Prion Diseases

The transmissible agent of prion disease consists of prion protein (PrP) in beta-sheet-rich state (PrPSc) that can replicate its conformation according to a template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide accurately reproduces that of the PrPSc template. Here, three conformationally distinct amyloid states were prepared in vitro using Syrian hamster recombinant PrP (rPrP) in the absence of cellular cofactors. Surprisingly, no signs of prion infection were found in Syrian hamsters inoculated with rPrP fibrils that resembled PrPSc, whereas an alternative amyloid state, with a folding pattern different from that of PrPSc, induced a pathogenic process that led to transmissible prion disease. An atypical proteinase K-resistant, transmissible PrP form that resembled the structure of the amyloid seeds was observed during a clinically silent stage before authentic PrPSc emerged. The dynamics between the two forms suggest that atypical proteinase K-resistant PrP (PrPres) gave rise to PrPSc. While no PrPSc was found in preparations of fibrils using protein misfolding cyclic amplification with beads (PMCAb), rPrP fibrils gave rise to atypical PrPres in modified PMCAb, suggesting that atypical PrPres was the first product of PrPC misfolding triggered by fibrils. The current work demonstrates that a new mechanism responsible for prion diseases different from the PrPSc-templated or spontaneous conversion of PrPC into PrPSc exists. This study provides compelling evidence that noninfectious amyloids with a structure different from that of PrPSc could lead to transmissible prion disease. This work has numerous implications for understanding the etiology of prion and other neurode generative diseases.