Soluble Dimeric Prion Protein Binds PrP(Sc) in Vivo and Antagonizes Prion Disease

Cell. 2003 Apr 4;113(1):49-60. doi: 10.1016/s0092-8674(03)00201-0.

Abstract

Conversion of cellular prion protein (PrP(C)) into a pathological conformer (PrP(Sc)) is thought to be promoted by PrP(Sc) in a poorly understood process. Here, we report that in wild-type mice, the expression of PrP(C) rendered soluble and dimeric by fusion to immunoglobulin Fcgamma (PrP-Fc(2)) delays PrP(Sc) accumulation, agent replication, and onset of disease following inoculation with infective prions. In infected PrP-expressing brains, PrP-Fc(2) relocates to lipid rafts and associates with PrP(Sc) without acquiring protease resistance, indicating that PrP-Fc(2) resists conversion. Accordingly, mice expressing PrP-Fc(2) but lacking endogenous PrP(C) are resistant to scrapie, do not accumulate PrP-Fc(2)(Sc), and do not transmit disease to others. These results indicate that various PrP isoforms engage in a complex in vivo, whose distortion by PrP-Fc(2) affects prion propagation and scrapie pathogenesis. The unique properties of PrP-Fc(2) suggest that soluble PrP derivatives may represent a new class of prion replication antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Disease Models, Animal
  • Drug Resistance / physiology
  • Endopeptidases / metabolism
  • Ligands
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • PrPC Proteins / genetics
  • PrPC Proteins / metabolism*
  • PrPC Proteins / therapeutic use
  • PrPSc Proteins / antagonists & inhibitors
  • PrPSc Proteins / metabolism*
  • Precipitin Tests
  • Prion Diseases / drug therapy
  • Prion Diseases / genetics
  • Prion Diseases / metabolism*
  • Prions / antagonists & inhibitors
  • Prions / metabolism*
  • Prions / pathogenicity
  • Protein Isoforms / drug effects
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism*
  • Receptors, IgG / therapeutic use
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Recombinant Fusion Proteins / therapeutic use
  • Scrapie / drug therapy
  • Scrapie / genetics
  • Scrapie / metabolism

Substances

  • Ligands
  • PrPC Proteins
  • PrPSc Proteins
  • Prions
  • Protein Isoforms
  • Receptors, IgG
  • Recombinant Fusion Proteins
  • Endopeptidases