Summary
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.
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References
Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181: 223–230
Bennett MJ, Schlunegger MP, Eisenberg D (1995) 3D domain swapping: a mechanism for oligomer assembly. Protein Sci 4: 2455–2468
Bessen RA, Marsh RF (1992) Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 66: 2096–2101
Bessen RA, Marsh RF (1994) Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 68: 7859–7868
Borchelt DR, Scott M, Taraboulos A, Stahl N, Prusiner SB (1990) Scrapie and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells. J Cell Biol 110: 743–752
Bruce ME, Dickinson AG (1987) Biological evidence that the scrapie agent has an independent genome. J Gen Virol 68: 79–89
Caughey B, Raymond GJ (1991) The scrapie-associated form of PrP is made from a cell surface precursor that is both protease- and phospholipase-sensitive. J Biol Chem 266: 18217–18223
Cohen FE, Prusiner SB (1998) Pathologic conformations of prion proteins. Annu Rev Biochem 67: 793–819
Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of “new variant” CJD. Nature 383: 685–690
DeArmond SJ, Sánchez H, Yehiely F, Qiu Y, Ninchak-Casey A, Daggett V, Camerino AP, Cayetano J, Rogers M, Groth D, Torchia M, Tremblay P, Scott MR, Cohen FE, Prusiner SB (1997) Selective neuronal targeting in prion disease. Neuron 19: 1337–1348
Dickinson AG, Fraser HG (1977) Scrapie: pathogenesis in inbred mice: an assessment of host control and response involving many strains of agent. In: ter Meulen V, Katz M (eds) Slow virus infections of the central nervous system. Springer, New York, pp 3–14
Dickinson AG, Outram GW (1988) Genetic aspects of unconventional virus infections: the basis of the virino hypothesis. In: Bock G, Marsh J (eds) Novel infectious agents and the central nervous system. J Wiley, Chichester, pp 63–83 (Ciba Foundation Symposium 135)
Endo T, Groth D, Prusiner SB, Kobata A (1989) Diversity of oligosaccharide structures linked to asparagines of the scrapie prion protein. Biochemistry 28: 8380–8388
Fraser H, Dickinson AG (1973) Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. J Comp Pathol 83: 29–40
Kaneko K, Zulianello L, Scott M, Cooper CM, Wallace AC, James TL, Cohen FE, Prusiner SB (1997) Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc Natl Acad Sci USA 94: 10069–10074
Kellings K, Meyer N, Mirenda C, Prusiner SB, Riesner D (1992) Further analysis of nucleic acids in purified scrapie prion preparations by improved return refocussing gel electrophoresis (RRGE). J Gen Virol 73: 1025–1029
Kellings K, Prusiner SB, Riesner D (1994) Nucleic acids in prion preparations: unspecific background or essential component? Phil Trans R Soc London Ser B 343: 425–430
Kimberlin RH, Cole S, Walker CA (1987) Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J Gen Virol 68: 1875–1881
Kimberlin RH, Walker CA (1978) Pathogenesis of mouse scrapie: effect of route of inoculation on infectivity titres and dose-response curves. J Comp Pathol 88: 39–47
Meyer N, Rosenbaum V, Schmidt B, Gilles K, Mirenda C, Groth D, Prusiner SB, Riesner D (1991) Search for a putative scrapie genome in purified prion fractions reveals a paucity of nucleic acids. J Gen Virol 72: 37–49
Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG, Farlow M, Dickson DW, Sima AAF, Trojanowski JQ, Petersen RB, Gambetti P (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39: 767–778
Pattison IH, Millson GC (1961) Scrapie produced experimentally in goats with special reference to the clinical syndrome. J Comp Pathol 71: 101–108
Prusiner SB (1991) Molecular biology of prion diseases. Science 252: 1515–1522
Prusiner SB (1997) Prion diseases and the BSE crisis. Science 278: 245–251
Prusiner SB (1998) Prions (Les Prix Nobel Lecture). In: T. Frängsmyr (ed) Les Prix Nobel. Almqvist & Wiksell International, Stockholm, pp 268–323
Prusiner SB, Scott MR, DeArmond SJ, Cohen FE (1998) Prion protein biology. Cell 93: 337–348
Safar J, Roller PP, Gajdusek DC, Gibbs CJ Jr (1994) Scrapie amyloid (prion) protein has the conformational characteristics of an aggregated molten globule folding intermediate. Biochemistry 33: 8375–8383
Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, Cohen FE, Prusiner SB (1998) Eight prion strains have PrPSc molecules with different conformations. Nature Med 4: 1157–1165
Scott MR, Groth D, Tatzelt J, Torchia M, Tremblay P, DeArmond SJ, Prusiner SB (1997) Propagation of prion strains through specific conformers of the prion protein. J Virol 71: 9032–9044
Taraboulos A, Jendroska K, Serban D, Yang S-L, DeArmond SJ, Prusiner SB (1992) Regional mapping of prion proteins in brains. Proc Natl Acad Sci USA 89: 7620–7624
Taraboulos A, Rogers M, Borchelt DR, McKinley MP, Scott M, Serban D, Prusiner SB (1990) Acquisition of protease resistance by prion proteins in scrapie-infected cells does not require asparagine-linked glycosylation. Proc Natl Acad Sci USA 87: 8262–8266
Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274: 2079–2082
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Safar, J., Cohen, F.E., Prusiner, S.B. (2000). Quantitative traits of prion strains are enciphered in the conformation of the prion protein. In: Groschup, M.H., Kretzschmar, H.A. (eds) Prion Diseases. Archives of Virology. Supplementa, vol 16. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6308-5_22
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DOI: https://doi.org/10.1007/978-3-7091-6308-5_22
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