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Biophys J. Nov 2001; 81(5): 2517–2529.
PMCID: PMC1301721

Prion diseases: dynamics of the infection and properties of the bistable transition.

Abstract

Prion diseases are thought to result from a pathogenic, conformational change in a cellular protein, the prion protein. The pathogenic isoform seems to convert the normal isoform in an autocatalytic process. In contrast to the conditions used for in vitro studies of enzyme kinetics, the concentration of the catalyst is not much lower than that of the substrate in the course of infection. This feature may endow the system with a time-hierarchy allowing the pathogenic isoform to relax very slowly in the course of infection. This may contribute to the long incubation periods observed in prion diseases. The dynamic process of prion propagation, including turnover of the cellular prion protein, displays bistable properties. Sporadic prion diseases may result from a change in one of the parameters associated with metabolism of the prion protein. The bistable transition observed in sporadic disease is reversible, whereas that observed in cases of exogenous contamination is irreversible. This model is consistent with the occurrence of rare, sporadic forms of prion diseases. It may also explain why only some individuals of a cohort develop a prion disease following transient food contamination.

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Selected References

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  • Bellinger-Kawahara CG, Kempner E, Groth D, Gabizon R, Prusiner SB. Scrapie prion liposomes and rods exhibit target sizes of 55,000 Da. Virology. 1988 Jun;164(2):537–541. [PubMed]
  • Beringue V, Lamoury F, Adjou KT, Maignien T, Demoy M, Couvreur P, Dormont D. Pharmacological manipulation of early PrPres accumulation in the spleen of scrapie-infected mice. Arch Virol Suppl. 2000;(16):39–56. [PubMed]
  • Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B. Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature. 1995 Jun 22;375(6533):698–700. [PubMed]
  • Borchelt DR, Scott M, Taraboulos A, Stahl N, Prusiner SB. Scrapie and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells. J Cell Biol. 1990 Mar;110(3):743–752. [PMC free article] [PubMed]
  • Come JH, Fraser PE, Lansbury PT., Jr A kinetic model for amyloid formation in the prion diseases: importance of seeding. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5959–5963. [PMC free article] [PubMed]
  • Edskes HK, Gray VT, Wickner RB. The [URE3] prion is an aggregated form of Ure2p that can be cured by overexpression of Ure2p fragments. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1498–1503. [PMC free article] [PubMed]
  • Eigen M. Prionics or the kinetic basis of prion diseases. Biophys Chem. 1996 Dec 10;63(1):A1–18. [PubMed]
  • Fernandez-Bellot E, Guillemet E, Cullin C. The yeast prion [URE3] can be greatly induced by a functional mutated URE2 allele. EMBO J. 2000 Jul 3;19(13):3215–3222. [PMC free article] [PubMed]
  • Halfman CJ, Marcus F. A method for determining kinetic parameters at high enzyme concentrations. Biochem J. 1982 Apr 1;203(1):339–342. [PMC free article] [PubMed]
  • Harper JD, Lansbury PT., Jr Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem. 1997;66:385–407. [PubMed]
  • Harrison PM, Chan HS, Prusiner SB, Cohen FE. Conformational propagation with prion-like characteristics in a simple model of protein folding. Protein Sci. 2001 Apr;10(4):819–835. [PMC free article] [PubMed]
  • Jarrett JT, Lansbury PT., Jr Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell. 1993 Jun 18;73(6):1055–1058. [PubMed]
  • Kacser H, Small JR. How many phenotypes from one genotype? The case of Prion diseases. J Theor Biol. 1996 Oct 7;182(3):209–218. [PubMed]
  • Kellershohn N, Laurent M. Analysis of progress curves for a highly concentrated Michaelian enzyme in the presence or absence of product inhibition. Biochem J. 1985 Oct 1;231(1):65–74. [PMC free article] [PubMed]
  • Kellershohn N, Laurent M. Species barrier in prion diseases: a kinetic interpretation based on the conformational adaptation of the prion protein. Biochem J. 1998 Sep 15;334(Pt 3):539–545. [PMC free article] [PubMed]
  • Kim H, O'Rourke KI, Walter M, Purchase HG, Enck J, Shin TK. Immunohistochemical detection of scrapie prion proteins in clinically normal sheep in Pennsylvania. J Vet Diagn Invest. 2001 Jan;13(1):89–91. [PubMed]
  • Korth C, Kaneko K, Prusiner SB. Expression of unglycosylated mutated prion protein facilitates PrP(Sc) formation in neuroblastoma cells infected with different prion strains. J Gen Virol. 2000 Oct;81(Pt 10):2555–2563. [PubMed]
  • Laurent M. Prion diseases and the 'protein only' hypothesis: a theoretical dynamic study. Biochem J. 1996 Aug 15;318(Pt 1):35–39. [PMC free article] [PubMed]
  • Laurent M. Autocatalytic processes in cooperative mechanisms of prion diseases. FEBS Lett. 1997 Apr 21;407(1):1–6. [PubMed]
  • Laurent M. Bistability and the species barrier in prion diseases: stepping across the threshold or not. Biophys Chem. 1998 May 5;72(1-2):211–222. [PubMed]
  • Laurent M, Johannin G. Molecular clues to pathogenesis in prion diseases. Histol Histopathol. 1997 Apr;12(2):583–594. [PubMed]
  • Laurent M, Kellershohn N. Apparent co-operativity for highly concentrated Michaelian and allosteric enzymes. J Mol Biol. 1984 Apr 15;174(3):543–555. [PubMed]
  • Laurent M, Kellershohn N. Multistability: a major means of differentiation and evolution in biological systems. Trends Biochem Sci. 1999 Nov;24(11):418–422. [PubMed]
  • Manuelidis EE, Manuelidis L. A transmissible Creutzfeldt-Jakob disease-like agent is prevalent in the human population. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7724–7728. [PMC free article] [PubMed]
  • Masel J, Jansen VA, Nowak MA. Quantifying the kinetic parameters of prion replication. Biophys Chem. 1999 Mar 29;77(2-3):139–152. [PubMed]
  • Porcher E, Gatto M. Quantifying the dynamics of prion infection: a bifurcation analysis of Laurent's model. J Theor Biol. 2000 Jul 21;205(2):283–296. [PubMed]
  • Prusiner SB. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515–1522. [PubMed]
  • Prusiner SB, Scott MR, DeArmond SJ, Cohen FE. Prion protein biology. Cell. 1998 May 1;93(3):337–348. [PubMed]
  • Serio TR, Cashikar AG, Kowal AS, Sawicki GJ, Moslehi JJ, Serpell L, Arnsdorf MF, Lindquist SL. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science. 2000 Aug 25;289(5483):1317–1321. [PubMed]
  • Sklaviadis T, Dreyer R, Manuelidis L. Analysis of Creutzfeldt-Jakob disease infectious fractions by gel permeation chromatography and sedimentation field flow fractionation. Virus Res. 1992 Dec;26(3):241–254. [PubMed]
  • Sklaviadis TK, Manuelidis L, Manuelidis EE. Physical properties of the Creutzfeldt-Jakob disease agent. J Virol. 1989 Mar;63(3):1212–1222. [PMC free article] [PubMed]
  • Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science. 1996 Dec 20;274(5295):2079–2082. [PubMed]
  • Vilette D, Andreoletti O, Archer F, Madelaine MF, Vilotte JL, Lehmann S, Laude H. Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4055–4059. [PMC free article] [PubMed]
  • Westaway D, DeArmond SJ, Cayetano-Canlas J, Groth D, Foster D, Yang SL, Torchia M, Carlson GA, Prusiner SB. Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell. 1994 Jan 14;76(1):117–129. [PubMed]
  • Wille H, Prusiner SB, Cohen FE. Scrapie infectivity is independent of amyloid staining properties of the N-terminally truncated prion protein. J Struct Biol. 2000 Jun;130(2-3):323–338. [PubMed]

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