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

PLoS Pathogens

Michael Oldstone¹  Sukhvir Paul Mahal²  Charles Weissmann²  Maria Eugenia Herva²  Irena Suponitsky-Kroyter²  Joseph Jablonski²  Anja Maria Oelschlegel² 

[1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America;Department of Infectology, Scripps Florida, Jupiter, Florida, United States of America

关键词: Prions;    Animal prion diseases;    Prion diseases;    Cloning;    Tropism;    Activation energy;    Cell membranes;    Genetically modified animals;   

DOI  :  10.1371/journal.ppat.1002746

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY