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

J Safar1, F E Cohen, S B Prusiner

  • 1Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco 94143-0518, USA.

Archives of Virology. Supplementum
|February 24, 2001
PubMed

Insights

Prion strains exhibit distinct conformational properties and protease-sensitive fractions that correlate with incubation times. These findings suggest that prion disease progression is primarily influenced by clearance rates rather than formation rates.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Prion diseases are caused by misfolded prion proteins (PrPSc).
  • Prion strains exhibit distinct phenotypes and replication fidelities.
  • Qualitative strain characteristics do not fully explain quantitative traits like incubation time.

Purpose of the Study:

  • To investigate the conformational parameters and accumulation rates of PrPSc in different prion strains.
  • To determine the relationship between PrPSc characteristics and disease incubation times.

Main Methods:

  • Conformation-dependent immunoassay (CDI) to discriminate PrPSc conformers.
  • Analysis of PrPSc concentrations and equilibrium unfolding patterns.
  • Quantification of protease-sensitive PrPSc fractions.
  • Correlation analysis between protease-sensitive PrPSc and incubation times.

Main Results:

  • CDI successfully differentiated eight hamster-propagated prion strains based on unique PrPSc conformer concentrations.
  • Each strain displayed a unique equilibrium unfolding pattern.
  • A significant fraction of protease-sensitive PrPSc was identified in all strains.
  • A strong linear correlation (r = 0.94) was observed between the protease-sensitive PrPSc fraction and incubation time.

Conclusions:

  • Prion strain characteristics are defined by distinct PrPSc conformations and accumulation patterns.
  • The rate of PrPSc clearance, reflected by the protease-sensitive fraction, is a major determinant of prion disease incubation time.
  • These findings challenge the notion that incubation time is solely dictated by PrPSc formation rates.

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