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Updated: May 21, 2026
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Propagation of RML prions in mice expressing PrP devoid of GPI anchor leads to formation of a novel, stable prion
Sukhvir Paul Mahal1, Joseph Jablonski, Irena Suponitsky-Kroyter
1Department of Infectology, Scripps Florida, Jupiter, Florida, United States of America.
Abstract:
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.
Insights
Mice lacking the GPI anchor on PrP(C) protein can propagate prion strains, but alter their properties. This suggests the anchorless PrP(Sc) structure in these mice lowers the energy barrier for prion strain conversion.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Prion protein (PrP(C)) normally anchors to the cell membrane via a GPI anchor.
- In prion diseases, PrP(C) converts to pathogenic PrP(Sc).
- Mice engineered without GPI anchors (tgGPI⁻) accumulate anchorless PrP(Sc) extracellularly.
Purpose of the Study:
- To investigate if tgGPI⁻ mice can propagate prion strains despite altered PrP(Sc) structure and location.
- To determine if anchorless PrP(Sc) influences prion strain characteristics.
Main Methods:
- Prion strain propagation in tgGPI⁻ mice.
- Cell Panel Assay (CPA) to determine cell tropism.
- Quantification of proteinase K-resistant PrP(Sc) (PrP(res)) levels.
- Passage of prions back into wild-type mice.
Main Results:
- RML and ME7 prion strains propagated in tgGPI⁻ mice developed novel cell tropisms.
- PrP(res) levels were 25-50 times higher in infected tgGPI⁻ brains compared to wild-type.
- ME7 prions regained original properties upon transfer to wild-type mice.
- RML prions generated a new stable strain (SFL) after passage in tgGPI⁻ mice.
Conclusions:
- Anchorless PrP(Sc) in tgGPI⁻ mice can lead to the emergence of new prion strains.
- The GPI anchor may normally maintain a high activation energy barrier between prion conformations.
- tgGPI⁻ mice provide a model to study prion strain evolution and the role of the GPI anchor.
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