Mouse-hamster chimeric prion protein (PrP) devoid of N-terminal residues 23-88 restores susceptibility to 22L prions, but not to RML prions in PrP-knockout mice

PLoS One. 2014 Oct 16;9(10):e109737. doi: 10.1371/journal.pone.0109737. eCollection 2014.

Abstract

Prion infection induces conformational conversion of the normal prion protein PrPC, into the pathogenic isoform PrPSc, in prion diseases. It has been shown that PrP-knockout (Prnp0/0) mice transgenically reconstituted with a mouse-hamster chimeric PrP lacking N-terminal residues 23-88, or Tg(MHM2Δ23-88)/Prnp 0/0 mice, neither developed the disease nor accumulated MHM2ScΔ23-88 in their brains after inoculation with RML prions. In contrast, RML-inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice developed the disease with abundant accumulation of MHM2ScΔ23-88 in their brains. These results indicate that MHM2Δ23-88 itself might either lose or greatly reduce the converting capacity to MHM2ScΔ23-88, and that the co-expressing wild-type PrPC can stimulate the conversion of MHM2Δ23-88 to MHM2ScΔ23-88 in trans. In the present study, we confirmed that Tg(MHM2Δ23-88)/Prnp 0/0 mice remained resistant to RML prions for up to 730 days after inoculation. However, we found that Tg(MHM2Δ23-88)/Prnp 0/0 mice were susceptible to 22L prions, developing the disease with prolonged incubation times and accumulating MHM2ScΔ23-88 in their brains. We also found accelerated conversion of MHM2Δ23-88 into MHM2ScΔ23-88 in the brains of RML- and 22L-inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice. However, wild-type PrPSc accumulated less in the brains of these inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice, compared with RML- and 22L-inoculated Prnp 0/+ mice. These results show that MHM2Δ23-88 itself can convert into MHM2ScΔ23-88 without the help of the trans-acting PrPC, and that, irrespective of prion strains inoculated, the co-expressing wild-type PrPC stimulates the conversion of MHM2Δ23-88 into MHM2ScΔ23-88, but to the contrary, the co-expressing MHM2Δ23-88 disturbs the conversion of wild-type PrPC into PrPSc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Cricetinae
  • Disease Susceptibility
  • Male
  • Mice
  • Mice, Knockout
  • Prion Diseases / genetics
  • Prion Diseases / metabolism*
  • Prion Proteins
  • Prions / chemistry
  • Prions / genetics*
  • Prions / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics*
  • Recombinant Fusion Proteins / metabolism*

Substances

  • Prion Proteins
  • Prions
  • Prnp protein, mouse
  • Recombinant Fusion Proteins

Grants and funding

This work was partly supported by a Grant-in-Aid from the bovine spongiform encephalopathy (BSE) and other Prion Disease Control Project of the Ministry of Agriculture, Forestry and Fisheries of Japan, and Grants-in-Aid from the Research Committee of Prion Disease and Slow Virus infection, the Ministry of Health, Labour and Welfare of Japan. HM is partly supported by a Cooperative Research Grant of the Institute for Enzyme Research, the University of Tokushima. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.