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 invest...

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Bibliographic Details
Published in:PLoS pathogens 2012-06, Vol.8 (6), p.e1002746-e1002746
Main Authors: Mahal, Sukhvir Paul, Jablonski, Joseph, Suponitsky-Kroyter, Irena, Oelschlegel, Anja Maria, Herva, Maria Eugenia, Oldstone, Michael, Weissmann, Charles
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Brain
Cell culture
Cloning
Enzyme-Linked Immunosorbent Assay
Experiments
Gene expression
Health aspects
Medicine
Membrane Glycoproteins - deficiency
Mice
Mice, Inbred C57BL
Mice, Transgenic
Physiological aspects
Prions
Propagation
Protein Conformation
Proteins
PrPC Proteins - chemistry
PrPC Proteins - metabolism
PrPSc Proteins - chemistry
PrPSc Proteins - metabolism
Scrapie - metabolism
Scrapie - transmission
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1002746