Efficient inhibition of prion replication by PrP-Fc2 suggests that the prion is a PrPSc oligomer

Joanna Masel, Nicolas Genoud, Adriano Aguzzi

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Soluble dimeric prion protein (PrP-Fc2) binds to the disease-associated prion protein PrPSc, and inhibits prion replication when expressed in transgenic mice. Prion inhibition is effective even if PrP-Fc2 is expressed at low levels, suggesting that its affinity for PrPSc is higher than that of monomeric PrPC. Here, we model prion accumulation as an exponential replication cycle of prion elongation and breakage. The exponential growth rate corresponding to this cycle is reflected in the incubation period of the disease. We use a mathematical model to calculate the exponential growth rate, and fit the model to in vivo data on prion incubation times corresponding to different levels of PrP C and PrP-Fc2. We find an excellent fit of the model to the data. Surprisingly, targeting of PrPSc can be effective at concentrations of PrP-Fc2 lower than that of PrPC, even if PrP-Fc2 and PrPC have the same affinity for PrP Sc. The best fit of our model to data predicts that the replicative prion consists of PrPSc oligomers with a mean size of four to 15 units.

Original languageEnglish (US)
Pages (from-to)1243-1251
Number of pages9
JournalJournal of Molecular Biology
Volume345
Issue number5
DOIs
StatePublished - Feb 4 2005

Keywords

  • amyloid formation
  • kinetics
  • nucleated polymerization
  • replication mechanism
  • therapeutics

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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