Prion Diseases pp 227-235 | Cite as

Quantitative traits of prion strains are enciphered in the conformation of the prion protein

  • J. Safar
  • F. E. Cohen
  • S. B. Prusiner
Part of the Archives of Virology. Supplementa book series (ARCHIVES SUPPL, volume 16)


Variations in prions, which cause different disease phenotypes, are often referred to as strains. Strains replicate with a high degree of fidelity, which demands a mechanism that can account for this phenomenon. Prion strains differ by qualitative characteristics such as clinical symptoms, brain pathology, topology of accumulated PrPSc, and Western blot patterns of glycosylated or deglycosylated PrPSc. Since none of these qualitative features can directly explain quantitative strain traits such as incubation time or dose response, we analyzed conformational parameters of PrPSc and the rate of accumulation in different prion strains. Using the conformation-dependent immunoassay (CDI), we were able to discriminate among PrPSc molecules from eight different prion strains propagated in Syrian hamsters. CDI quantifies PrP isoforms by simultaneously following antibody binding to both the denatured and native forms of a protein. In a plot of the ratio of antibody binding to denatured/native PrP graphed as a function of the concentration of PrPSc, each strain occupied a unique position, indicating that each strain accumulated different concentrations of particular PrPSc conformers. This conclusion was supported by a unique pattern of equilibrium unfolding of PrPSc found within each strain. By comparing the PrPSc levels before and after limited proteinase K digestion, we found that each strain produces a substantial fraction of protease-sensitive PrPSc. We asked whether this fraction of PrPSc might reflect those PrPSc molecules that are most readily cleared by cellular proteases. When the protease-sensitive PrPSc fraction was plotted as a function of the incubation time, a linear relationship was found with an excellent correlation coefficient (r = 0.94). Combined with the data on time courses of prion infection in Tg(MHu2M) and Tg(SHaPrP) mice, the results argue that different incubation times of various prion strains may arise predominantly from distinct rates of PrPSc clearance rather than from different rates of PrPSc formation.


Prion Protein Prion Disease Syrian Hamster Prion Strain Scrapie Prion 
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Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • J. Safar
    • 1
    • 2
  • F. E. Cohen
    • 1
    • 3
    • 4
    • 5
  • S. B. Prusiner
    • 1
    • 2
    • 3
  1. 1.Institute for Neurodegenerative DiseasesUniversity of CaliforniaSan FranciscoUSA
  2. 2.Departments of NeurologyUniversity of CaliforniaSan FranciscoUSA
  3. 3.Departments of Biochemistry and BiophysicsUniversity of CaliforniaSan FranciscoUSA
  4. 4.Departments of MedicineUniversity of CaliforniaSan FranciscoUSA
  5. 5.Departments of Cellular and Molecular PharmacologyUniversity of CaliforniaSan FranciscoUSA

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