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

• Published in: PLoS pathogens Vol. 13; no. 7; p. e1006491
• Main Authors: Wang, Fei, Wang, Xinhe, Orrú, Christina D, Groveman, Bradley R, Surewicz, Krystyna, Abskharon, Romany, Imamura, Morikazu, Yokoyama, Takashi, Kim, Yong-Sun, Vander Stel, Kayla J, Sinniah, Kumar, Priola, Suzette A, Surewicz, Witold K, Caughey, Byron, Ma, Jiyan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2017; Public Library of Science (PLoS)
• Subjects: Agglomeration; Animals; Antibodies; Biocatalysis; Biochemistry; Biology and Life Sciences; Biophysics; Cofactors; Denaturation; Dimerization; Disease susceptibility; Endopeptidases - chemistry; Endopeptidases - metabolism; Funding; Genetic aspects; Guanidine hydrochloride; Health aspects; In vivo methods and tests; Infectious diseases; Lipids; Medicine and Health Sciences; Methods; Mice; Pathogenicity; Pathogens; Phosphatidylethanolamine; Phosphatidylglycerol; Phosphatidylglycerols - metabolism; Physiology; Prion Diseases - genetics; Prion Diseases - metabolism; Prion protein; Prion Proteins - chemistry; Prion Proteins - genetics; Prion Proteins - metabolism; Prions; Prions (Proteins); Protease; Protein Binding; Protein Conformation; Protein seeding; Protein structure; Proteinase; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Research and Analysis Methods; Ribonucleic acid; RNA; RNA - chemistry; RNA - genetics; RNA - metabolism; Roles; Science; Stochasticity; Supervision; Testing; Cleveland Ohio; Montana; Ohio; United States > US; Michigan
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006491

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.