Propagation of RML prions in mice expressing PrP devoid of GPI anchor leads to formation of a novel,stable prion strain

Prpc,a host protein which in prion-infected animals is converted to prpsc,is linked to the cell membrane by a gpi anchor. mice expressing prpc without gpi anchor (tggpi- mice),are susceptible to prion infection but accumulate anchorless prpsc extra-,rather than intracellularly. we investigated whether tggpi- mice could faithfully propagate prion strains despite the deviant structure and location of anchorless prpsc. 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 prpsc (prpres) 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 prpsc and sfl prpsc 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. © 2012 mahal et al.