Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein

摘要

Last decade witnessed an enormous progress in generating authentic infectious prions or PrP^Sc in vitro using recombinant prion protein (rPrP). Previous work established that rPrP that lacks posttranslational modification is able to support replication of highly infectious PrP^Sc with assistance of cofactors of polyanionic nature and/or lipids. Unexpectedly, previous studies also revealed that seeding of rPrP by brain-derived PrP^Sc gave rise to new prion strains with new disease phenotypes documenting loss of a strain identity upon replication in rPrP substrate. Up to now, it remains unclear whether prion strain identity can be preserved upon replication in rPrP. The current study reports that faithful replication of hamster strain SSLOW could be achieved in vitro using rPrP as a substrate. We found that a mixture of phosphatidylethanolamine (PE) and synthetic nucleic acid polyA was sufficient for stable replication of hamster brain-derived SSLOW PrP^Sc in serial Protein Misfolding Cyclic Amplification (sPMCA) that uses hamster rPrP as a substrate. The disease phenotype generated in hamsters upon transmission of recombinant PrP^Sc produced in vitro was strikingly similar to the original SSLOW diseases phenotype with respect to the incubation time to disease, as well as clinical, neuropathological and biochemical features. Infrared microspectroscopy (IR-MSP) indicated that PrP^Sc produced in animals upon transmission of recombinant PrP^Sc is structurally similar if not identical to the original SSLOW PrP^Sc. The current study is the first to demonstrate that rPrP can support replication of brain-derived PrP^Sc while preserving its strain identity. In addition, the current work is the first to document that successful propagation of a hamster strain could be achieved in vitro using hamster rPrP.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0597-y) contains supplementary material, which is available to authorized users.