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Propagation of rml prions in mice expressing prp devoid of gpi anchor leads to formation of a novel, stable prion strain

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Overview

authors

  • Mahal, S. P.
  • Jablonski, J.
  • Suponitsky-Kroyter, I.
  • Oelschlegel, A. M.
  • Herva, M. E.
  • Oldstone, Michael
  • Weissmann, Charles

publication date

  • June 2012

journal

  • PLoS Pathogens  Journal

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.
  • 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.

subject areas

  • Animals
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • PrPC Proteins
  • PrPSc Proteins
  • Protein Conformation
  • Scrapie
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Identity

PubMed Central ID

  • PMC3369955

International Standard Serial Number (ISSN)

  • 1553-7374

Digital Object Identifier (DOI)

  • 10.1371/journal.ppat.1002746

PubMed ID

  • 22685404
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Additional Document Info

start page

  • e1002746

volume

  • 8

issue

  • 6

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