Propagation of RML Prions in Mice Expressing PrP Devoid of GPI Anchor Leads to Formation of a Novel, Stable Prion Strain

PrP C , a host protein which in prion-infected animals is converted to PrP Sc , is linked to the cell membrane by a GPI anchor. Mice expressing PrP C without GPI anchor (tgGPI - mice), are susceptible to prion infection but accumulate anchorless PrP Sc extra-, rather than intracellularly. We investigated whether tgGPI − mice could faithfully propagate prion strains despite the deviant structure and location of anchorless PrP Sc . We found that RML and ME7, but not 22L prions propagated in tgGPI − brain developed novel cell tropisms, as determined by the Cell Panel Assay (CPA). Surprisingly, the levels of proteinase K-resistant PrP Sc (PrP res ) in RML- or ME7-infected tgGPI − brain were 25–50 times higher than in wild-type brain. When returned to wild-type brain, ME7 prions recovered their original properties, however RML prions had given rise to a novel prion strain, designated SFL, which remained unchanged even after three passages in wild-type mice. Because both RML PrP Sc and SFL PrP Sc are stably propagated in wild-type mice we propose that the two conformations are separated by a high activation energy barrier which is abrogated in tgGPI − mice.