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

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. © 2017 public library of science. all rights reserved.