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.
Department of Infectology, Scripps Florida, Jupiter, Florida, United States of America.
Sukhvir Paul
SP
Mahal
Joseph
J
Jablonski
Irena
I
Suponitsky-Kroyter
Anja Maria
AM
Oelschlegel
Maria Eugenia
ME
Herva
Michael
M
Oldstone
Charles
C
Weissmann
D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018621:PrPC Proteins / Q000737:chemistry* / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D012608:Scrapie / Q000378:metabolism / Q000635:transmission*
C486253:Gpaa1 protein, mouse; D008562:Membrane Glycoproteins; D018621:PrPC Proteins; D018620:PrPSc Proteins