4 years ago

Self-propagating, protease-resistant, recombinant prion protein conformers with or without <i>in vivo</i> pathogenicity

Xinhe Wang, Suzette A. Priola, Fei Wang, Jiyan Ma, Morikazu Imamura, Takashi Yokoyama, Krystyna Surewicz, Christina D. Orrú, Kumar Sinniah, Romany Abskharon, Byron Caughey, Bradley R. Groveman, Kayla J. Vander Stel, Yong-Sun Kim, Witold K. Surewicz

by Fei Wang, Xinhe Wang, Christina D. Orrú, Bradley R. Groveman, Krystyna Surewicz, Romany Abskharon, Morikazu Imamura, Takashi Yokoyama, Yong-Sun Kim, Kayla J. Vander Stel, Kumar Sinniah, Suzette A. Priola, Witold K. Surewicz, Byron Caughey, Jiyan Ma

Prions, characterized by self-propagating protease-resistant prion protein (PrP) conformations, are agents causing prion disease. Recent studies generated several such self-propagating protease-resistant recombinant PrP (rPrP-res) conformers. While some cause prion disease, others fail to induce any pathology. Here we showed that although distinctly different, the pathogenic and non-pathogenic rPrP-res conformers were similarly recognized by a group of conformational antibodies against prions and shared a similar guanidine hydrochloride denaturation profile, suggesting a similar overall architecture. Interestingly, two independently generated non-pathogenic rPrP-res were almost identical, indicating that the particular rPrP-res resulted from cofactor-guided PrP misfolding, rather than stochastic PrP aggregation. Consistent with the notion that cofactors influence rPrP-res conformation, the propagation of all rPrP-res formed with phosphatidylglycerol/RNA was cofactor-dependent, which is different from rPrP-res generated with a single cofactor, phosphatidylethanolamine. Unexpectedly, despite the dramatic difference in disease-causing capability, RT-QuIC assays detected large increases in seeding activity in both pathogenic and non-pathogenic rPrP-res inoculated mice, indicating that the non-pathogenic rPrP-res is not completely inert in vivo. Together, our study supported a role of cofactors in guiding PrP misfolding, indicated that relatively small structural features determine rPrP-res’ pathogenicity, and revealed that the in vivo seeding ability of rPrP-res does not necessarily result in pathogenicity.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.ppat.1006491

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