Sheep scrapie susceptibility-linked polymorphisms do not modulate the initial binding of cellular to disease-associated prion protein prior to conversion Free

Abstract

Conversion of the host-encoded protease-sensitive cellular prion protein (PrP) into the scrapie-associated protease-resistant isoform (PrP) of prion protein (PrP) is the central event in transmissible spongiform encephalopathies or prion diseases. Differences in transmissibility and susceptibility are largely determined by polymorphisms in PrP, but the exact molecular mechanism behind PrP conversion and the modulation by disease-associated polymorphisms is still unclear. To assess whether the polymorphisms in either PrP or PrP modulate the initial binding of PrP to PrP, several naturally occurring allelic variants of sheep PrP and PrP that are associated with differential scrapie susceptibility and transmissibility [the phylogenetic wild-type (ARQ), the codon 136Val variant (VRQ) and the codon 171Arg variant (ARR)] were used. Under cell-free PrP conversion conditions known to reproduce the observed differential scrapie susceptibility, it was found that the relative amounts of PrP allelic variants bound by various allelic PrP variants are PrP-specific and have comparable binding efficiencies. Therefore, the differential rate-limiting step in conversion of sheep PrP variants is not determined by the initial PrP–PrP-binding efficiency, but seems to be an intrinsic property of PrP itself. Consequently, a second step after PrP–PrP-binding should determine the observed differences in PrP conversion efficiencies. Further study of this second step may provide a future tool to determine the mechanism underlying refolding of PrP into PrP and supports the use of conversion-resistant polymorphic PrP variants as a potential therapeutic approach to interfere with PrP conversion in transmissible spongiform encephalopathy development.

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2005-09-01
2024-03-28
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References

  1. Belt P. B., Muileman I. H., Schreuder B. E., Bos-de Ruijter J., Gielkens A. L., Smits M. A. 1995; Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie. J Gen Virol 76:509–517 [CrossRef]
    [Google Scholar]
  2. Belt P. B. G. M., Bossers A., Schreuder B. E. C., Smits M. A. 1996; PrP allelic variants associated with natural scrapie. In Bovine Spongiform Encephalopathy; The BSE Dilemma pp  294–305 Edited by Gibbs C. J. Jr New York: Springer;
    [Google Scholar]
  3. Bossers A. 1999 Prion Disease: Susceptibility and Transmissibility; In Vivo and In Vitro Studies with Sheep Scrapie University of Utrecht;
    [Google Scholar]
  4. Bossers A., Schreuder B. E., Muileman I. H., Belt P. B., Smits M. A. 1996; PrP genotype contributes to determining survival times of sheep with natural scrapie. J Gen Virol 77:2669–2673 [CrossRef]
    [Google Scholar]
  5. Bossers A., Belt P. B. G. M., Raymond G. J., Caughey B., de Vries R., Smits M. A. 1997; Scrapie susceptibility-linked polymorphisms modulate the in vitro conversion of sheep prion protein to protease-resistant forms. Proc Natl Acad Sci U S A 94:4931–4936 [CrossRef]
    [Google Scholar]
  6. Bossers A., Harders F. L., Smits M. A. 1999; PrP genotype frequencies of the most dominant sheep breed in a country free from scrapie. Arch Virol 144:829–834 [CrossRef]
    [Google Scholar]
  7. Bossers A., de Vries R., Smits M. A. 2000; Susceptibility of sheep for scrapie as assessed by in vitro conversion of nine naturally occurring variants of PrP. J Virol 74:1407–1414 [CrossRef]
    [Google Scholar]
  8. Bossers A., Rigter A., de Vries R., Smits M. A. 2003; In vitro conversion of normal prion protein into pathologic isoforms. In Clin Lab Med pp  227–247 Edited by Ghetti MD B., Piccardo MD P. W. B. Saunders Company, a division of Elsevier Science;
    [Google Scholar]
  9. Caplazi P. A., O'Rourke K. I., Baszler T. V. 2004; Resistance to scrapie in PrP ARR/ARQ heterozygous sheep is not caused by preferential allelic use. J Clin Pathol 57:647–650 [CrossRef]
    [Google Scholar]
  10. Caughey B., Kocisko D. A., Raymond G. J., Lansbury P. T. Jr 1995; Aggregates of scrapie-associated prion protein induce the cell-free conversion of protease-sensitive prion protein to the protease-resistant state. Chem Biol 2:807–817 [CrossRef]
    [Google Scholar]
  11. Caughey B., Raymond G. J., Kocisko D. A., Lansbury P. T. Jr 1997; Scrapie infectivity correlates with converting activity, protease resistance, and aggregation of scrapie-associated prion protein in guanidine denaturation studies. J Virol 71:4107–4110
    [Google Scholar]
  12. Clouscard C., Beaudry P., Elsen J. M. 7 other authors 1995; Different allelic effects of the codons 136 and 171 of the prion protein gene in sheep with natural scrapie. J Gen Virol 76:2097–2101 [CrossRef]
    [Google Scholar]
  13. Collinge J., Palmer M. S., Dryden A. J. 1991; Genetic predisposition to iatrogenic Creutzfeldt–Jakob disease. Lancet 337:1441–1442 [CrossRef]
    [Google Scholar]
  14. DeArmond S. J., Prusiner S. B. 2003; Perspectives on prion biology, prion disease pathogenesis, and pharmacologic approaches to treatment. Clin Lab Med 23:1–41 [CrossRef]
    [Google Scholar]
  15. Dubois M. A., Sabatier P., Durand B., Calavas D., Ducrot C., Chalvet-Monfray K. 2002; Multiplicative genetic effects in scrapie disease susceptibility. C R Biol 325:565–570 [CrossRef]
    [Google Scholar]
  16. Eghiaian F., Grosclaude J., Lesceu S., Debey P., Doublet B., Treguer E., Rezaei H., Knossow M. 2004; Insight into the PrPC→PrPSc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants. Proc Natl Acad Sci U S A 101:10254–10259 [CrossRef]
    [Google Scholar]
  17. Elsen J. M., Amigues Y., Schelcher F. 7 other authors 1999; Genetic susceptibility and transmission factors in scrapie: detailed analysis of an epidemic in a closed flock of Romanov. Arch Virol 144:431–445 [CrossRef]
    [Google Scholar]
  18. Goldmann W., Hunter N., Foster J. D., Salbaum J. M., Beyreuther K., Hope J. 1990; Two alleles of a neural protein gene linked to scrapie in sheep. Proc Natl Acad Sci U S A 87:2476–2480 [CrossRef]
    [Google Scholar]
  19. Goldmann W., Hunter N., Benson G., Foster J. D., Hope J. 1991; Different scrapie-associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the Sip gene. J Gen Virol 72:2411–2417 [CrossRef]
    [Google Scholar]
  20. Goldmann W., Hunter N., Smith G., Foster J., Hope J. 1994; PrP genotypes and the Sip gene in Cheviot sheep form the basis for scrapie strain typing in sheep. Ann N Y Acad Sci 724:296–299 [CrossRef]
    [Google Scholar]
  21. Holscher C., Delius H., Burkle A. 1998; Overexpression of nonconvertible PrP C Δ114–121 in scrapie-infected mouse neuroblastoma cells leads to trans -dominant inhibition of wild-type PrP Sc accumulation. J Virol 72:1153–1159
    [Google Scholar]
  22. Horiuchi M., Priola S. A., Chabry J., Caughey B. 2000; Interactions between heterologous forms of prion protein: binding, inhibition of conversion, and species barriers. Proc Natl Acad Sci U S A 97:5836–5841 [CrossRef]
    [Google Scholar]
  23. Hunter N., Foster J. D., Goldmann W., Stear M. J., Hope J., Bostock C. 1996; Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes. Arch Virol 141:809–824 [CrossRef]
    [Google Scholar]
  24. Junghans F., Teufel B., Buschmann A., Steng G., Groschup M. H. 1998; Genotyping of German sheep with respect to scrapie susceptibility. Vet Rec 143:340–341 [CrossRef]
    [Google Scholar]
  25. McCullagh P. N. J. A. 1983 Genized linear models , 1st edn. Edited by McCullagh P., Nelder J. A. London, England: Chapman & Hall;
    [Google Scholar]
  26. O'Rourke K. I., Baszler T. V., Besser T. E. 9 other authors 2000; Preclinical diagnosis of scrapie by immunohistochemistry of third eyelid lymphoid tissue. J Clin Microbiol 38:3254–3259
    [Google Scholar]
  27. Palmer M. S., Dryden A. J., Hughes J. T., Collinge J. 1991; Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature 352:340–342 [CrossRef]
    [Google Scholar]
  28. Perrier V., Kaneko K., Safar J., Vergara J., Tremblay P., DeArmond S. J., Cohen F. E., Prusiner S. B., Wallace A. C. 2002; Dominant-negative inhibition of prion replication in transgenic mice. Proc Natl Acad Sci U S A 99:13079–13084 [CrossRef]
    [Google Scholar]
  29. Priola S. A., Lawson V. A. 2001; Glycosylation influences cross-species formation of protease-resistant prion protein. EMBO J 20:6692–6699 [CrossRef]
    [Google Scholar]
  30. Priola S. A., Caughey B., Race R. E., Chesebro B. 1994; Heterologous PrP molecules interfere with accumulation of protease-resistant PrP in scrapie-infected murine neuroblastoma cells. J Virol 68:4873–4878
    [Google Scholar]
  31. Raymond G. J., Hope J., Kocisko D. A. 12 other authors 1997; Molecular assessment of the potential transmissibilities of BSE and scrapie to humans. Nature 388:285–288 [CrossRef]
    [Google Scholar]
  32. Raymond G. J., Bossers A., Raymond L. D. 7 other authors 2000; Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease. EMBO J 19:4425–4430 [CrossRef]
    [Google Scholar]
  33. Rezaei H., Choiset Y., Eghiaian F., Treguer E., Mentre P., Debey P., Grosclaude J., Haertle T. 2002; Amyloidogenic unfolding intermediates differentiate sheep prion protein variants. J Mol Biol 322:799–814 [CrossRef]
    [Google Scholar]
  34. Sabuncu E., Petit S., Le Dur A., Lan Lai T., Vilotte J. L., Laude H., Vilette D. 2003; PrP polymorphisms tightly control sheep prion replication in cultured cells. J Virol 77:2696–2700 [CrossRef]
    [Google Scholar]
  35. Thorgeirsdottir S., Sigurdarson S., Thorisson H. M., Georgsson G., Palsdottir A. 1999; PrP gene polymorphism and natural scrapie in Icelandic sheep. J Gen Virol 80:2527–2534
    [Google Scholar]
  36. Tranulis M. A. 2002; Influence of the prion protein gene, Prnp, on scrapie susceptibility in sheep. APMIS 110:33–43 [CrossRef]
    [Google Scholar]
  37. Tranulis M. A., Osland A., Bratberg B., Ulvund M. J. 1999; Prion protein gene polymorphisms in sheep with natural scrapie and healthy controls in Norway. J Gen Virol 80:1073–1077
    [Google Scholar]
  38. van Gennip H. G., Bouma A., van Rijn P. A., Widjojoatmodjo M. N., Moormann R. J. 2002; Experimental non-transmissible marker vaccines for classical swine fever (CSF) by trans -complementation of Erns or E2 of CSFV. Vaccine 20:1544–1556 [CrossRef]
    [Google Scholar]
  39. van Keulen L. J., Schreuder B. E., Meloen R. H., Poelen-van den Berg M., Mooij-Harkes G., Vromans M. E., Langeveld J. P. 1995; Immunohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Vet Pathol 32:299–308 [CrossRef]
    [Google Scholar]
  40. Wensvoort G. 1989; Topographical and functional mapping of epitopes on hog cholera virus with monoclonal antibodies. J Gen Virol 70:2865–2876 [CrossRef]
    [Google Scholar]
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