1887

Abstract

Native mammalian prions exist in self-propagating strains that exhibit distinctive clinical, pathological and biochemical characteristics. Prion strain diversity is associated with variations in PrP conformation, but it remains unknown precisely which physical properties of the PrP molecules are required to encipher mammalian prion strain phenotypes. In this study, we subjected prion-infected brain homogenates derived from three different hamster scrapie strains to either (i) proteinase K digestion or (ii) sonication, and inoculated the modified samples into normal hamsters. The results show that the strain-specific clinical features and neuropathological profiles of inoculated animals were not affected by either treatment. Similarly, the strain-dependent biochemical characteristics of the PrP molecules (including electrophoretic mobility, glycoform composition, conformational stability and susceptibility to protease digestion) in infected animals were unaffected by either proteolysis or sonication of the original inocula. These results indicate that the infectious strain properties of native prions do not appear to be altered by PrP disaggregation, and that maintenance of such properties does not require the N-domain (approximately residues 23–90) of the protease-resistant PrP molecules or protease-sensitive PrP molecules.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.2008/002303-0
2008-10-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/10/2642.html?itemId=/content/journal/jgv/10.1099/vir.0.2008/002303-0&mimeType=html&fmt=ahah

References

  1. Barron R. M., Thomson V., Jamieson E., Melton D. W., Ironside J., Will R., Manson J. C. 2001; Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO J 20:5070–5078 [CrossRef]
    [Google Scholar]
  2. Barron R. M., Campbell S. L., King D., Bellon A., Chapman K. E., Williamson R. A., Manson J. C. 2007; High titers of transmissible spongiform encephalopathy infectivity associated with extremely low levels of PrPSc in vivo . J Biol Chem 282:35878–35886 [CrossRef]
    [Google Scholar]
  3. Bessen R. A., Marsh R. F. 1992; Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 66:2096–2101
    [Google Scholar]
  4. Bessen R. A., Marsh R. F. 1994; Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 68:7859–7868
    [Google Scholar]
  5. Brown P., Gajdusek D. C. 1991; Survival of scrapie virus after 3 years' interment. Lancet 337:269–270 [CrossRef]
    [Google Scholar]
  6. Bruce M. E. 1993; Scrapie strain variation and mutation. Br Med Bull 49:822–838
    [Google Scholar]
  7. Burns C. S., Aronoff-Spencer E., Legname G., Prusiner S. B., Antholine W. E., Gerfen G. J., Peisach J., Millhauser G. L. 2003; Copper coordination in the full-length, recombinant prion protein. Biochemistry 42:6794–6803 [CrossRef]
    [Google Scholar]
  8. Carlson G. A. 1996; Prion strains. Curr Top Microbiol Immunol 207:35–47
    [Google Scholar]
  9. Castilla J., Saa P., Hetz C., Soto C. 2005; In vitro generation of infectious scrapie prions. Cell 121:195–206 [CrossRef]
    [Google Scholar]
  10. Collinge J., Sidle K. C., Meads J., Ironside J., Hill A. F. 1996; Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383:685–690 [CrossRef]
    [Google Scholar]
  11. DeArmond S. J., Yang S. L., Lee A., Bowler R., Taraboulos A., Groth D., Prusiner S. B. 1993; Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform. Proc Natl Acad Sci U S A 90:6449–6453 [CrossRef]
    [Google Scholar]
  12. Deleault N. R., Harris B. T., Rees J. R., Supattapone S. 2007; Formation of native prions from minimal components in vitro . Proc Natl Acad Sci U S A 104:9741–9746 [CrossRef]
    [Google Scholar]
  13. Dickinson A. G., Fraser H. 1969; Modification of the pathogenesis of scrapie in mice by treatment of the agent. Nature 222:892–893 [CrossRef]
    [Google Scholar]
  14. Endo T., Groth D., Prusiner S. B., Kobata A. 1989; Diversity of oligosaccharide structures linked to asparagines of the scrapie prion protein. Biochemistry 28:8380–8388 [CrossRef]
    [Google Scholar]
  15. Fraser H., Dickinson A. G. 1967; Distribution of experimentally induced scrapie lesions in the brain. Nature 216:1310–1311 [CrossRef]
    [Google Scholar]
  16. Gabizon R., McKinley M. P., Groth D. F., Kenaga L., Prusiner S. B. 1988; Properties of scrapie prion protein liposomes. J Biol Chem 263:4950–4955
    [Google Scholar]
  17. Glatzel M., Stoeck K., Seeger H., Luhrs T., Aguzzi A. 2005; Human prion diseases: molecular and clinical aspects. Arch Neurol 62:545–552 [CrossRef]
    [Google Scholar]
  18. Holada K., Simak J., Vostal J. G. 2000; Transmission of BSE by blood transfusion. Lancet 356:1772 [CrossRef]
    [Google Scholar]
  19. Hopkins T. R. 1991; Physical and chemical cell disruption for the recovery of intracellular proteins. Bioprocess Technol 12:57–83
    [Google Scholar]
  20. Jackson G. S., Murray I., Hosszu L. L., Gibbs N., Waltho J. P., Clarke A. R., Collinge J. 2001; Location and properties of metal-binding sites on the human prion protein. Proc Natl Acad Sci U S A 98:8531–8535 [CrossRef]
    [Google Scholar]
  21. Jones C. E., Klewpatinond M., Abdelraheim S. R., Brown D. R., Viles J. H. 2005; Probing copper2+ binding to the prion protein using diamagnetic nickel2+ and 1H NMR: the unstructured N terminus facilitates the coordination of six copper2+ ions at physiological concentrations. J Mol Biol 346:1393–1407 [CrossRef]
    [Google Scholar]
  22. Ligios C., Sigurdson C. J., Santucciu C., Carcassola G., Manco G., Basagni M., Maestrale C., Cancedda M. G., Madau L., Aguzzi A. 2005; PrPSc in mammary glands of sheep affected by scrapie and mastitis. Nat Med 11:1137–1138 [CrossRef]
    [Google Scholar]
  23. Locht C., Chesebro B., Race R., Keith J. M. 1986; Molecular cloning and complete sequence of prion protein cDNA from mouse brain infected with the scrapie agent. Proc Natl Acad Sci U S A 83:6372–6376 [CrossRef]
    [Google Scholar]
  24. Mathiason C. K., Powers J. G., Dahmes S. J., Osborn D. A., Miller K. V., Warren R. J., Mason G. L., Hays S. A., Hayes-Klug J. other authors 2006; Infectious prions in the saliva and blood of deer with chronic wasting disease. Science 314:133–136 [CrossRef]
    [Google Scholar]
  25. Pastrana M. A., Sajnani G., Onisko B., Castilla J., Morales R., Soto C., Requena J. R. 2006; Isolation and characterization of a proteinase K-sensitive PrPSc fraction. Biochemistry 45:15710–15717 [CrossRef]
    [Google Scholar]
  26. Peretz D., Scott M. R., Groth D., Williamson R. A., Burton D. R., Cohen F. E., Prusiner S. B. 2001; Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 10:854–863 [CrossRef]
    [Google Scholar]
  27. Peretz D., Supattapone S., Giles K., Vergara J., Freyman Y., Lessard P., Safar J. G., Glidden D. V., McCulloch C. other authors 2006; Inactivation of prions by acidic sodium dodecyl sulfate. J Virol 80:322–331 [CrossRef]
    [Google Scholar]
  28. Prusiner S. B. 1982; Novel proteinaceous infectious particles cause scrapie. Science 216:136–144 [CrossRef]
    [Google Scholar]
  29. Prusiner S. B., McKinley M. P., Bowman K. A., Bolton D. C., Bendheim P. E., Groth D. F., Glenner G. G. 1983; Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 35:349–358 [CrossRef]
    [Google Scholar]
  30. Prusiner S. B., Groth D. F., Bolton D. C., Kent S. B., Hood L. E. 1984; Purification and structural studies of a major scrapie prion protein. Cell 38:127–134 [CrossRef]
    [Google Scholar]
  31. Safar J., Wille H., Itri V., Groth D., Serban H., Torchia M., Cohen F. E., Prusiner S. B. 1998; Eight prion strains have PrPSc molecules with different conformations. Nat Med 4:1157–1165 [CrossRef]
    [Google Scholar]
  32. Seeger H., Heikenwalder M., Zeller N., Kranich J., Schwarz P., Gaspert A., Seifert B., Miele G., Aguzzi A. 2005; Coincident scrapie infection and nephritis lead to urinary prion excretion. Science 310:324–326 [CrossRef]
    [Google Scholar]
  33. Somerville R. A., Carp R. I. 1983; Altered scrapie infectivity estimates by titration and incubation period in the presence of detergents. J Gen Virol 64:2045–2050 [CrossRef]
    [Google Scholar]
  34. Stahl N., Borchelt D. R., Hsiao K., Prusiner S. B. 1987; Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 51:229–240 [CrossRef]
    [Google Scholar]
  35. Supattapone S., Muramoto T., Legname G., Mehlhorn I., Cohen F. E., DeArmond S. J., Prusiner S. B., Scott M. R. 2001; Identification of two prion protein regions that modify scrapie incubation time. J Virol 75:1408–1413 [CrossRef]
    [Google Scholar]
  36. Taylor D. M., Fernie K. 1996; Exposure to autoclaving or sodium hydroxide extends the dose-response curve of the 263K strain of scrapie agent in hamsters. J Gen Virol 77:811–813 [CrossRef]
    [Google Scholar]
  37. Taylor D. R., Hooper N. M. 2007; The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein. Biochem J 402:17–23 [CrossRef]
    [Google Scholar]
  38. Telling G. C., Parchi P., DeArmond S. J., Cortelli P., Montagna P., Gabizon R., Mastrianni J., Lugaresi E., Gambetti P., Prusiner S. B. 1996; Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082 [CrossRef]
    [Google Scholar]
  39. Turk E., Teplow D. B., Hood L. E., Prusiner S. B. 1988; Purification and properties of the cellular and scrapie hamster prion proteins. Eur J Biochem 176:21–30 [CrossRef]
    [Google Scholar]
  40. Viles J. H., Cohen F. E., Prusiner S. B., Goodin D. B., Wright P. E., Dyson H. J. 1999; Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc Natl Acad Sci U S A 96:2042–2047 [CrossRef]
    [Google Scholar]
  41. Warner R. G., Hundt C., Weiss S., Turnbull J. E. 2002; Identification of the heparan sulfate binding sites in the cellular prion protein. J Biol Chem 277:18421–18430 [CrossRef]
    [Google Scholar]
  42. Wickner R. B., Edskes H. K., Shewmaker F., Nakayashiki T. 2007; Prions of fungi: inherited structures and biological roles. Nat Rev Microbiol 5:611–618 [CrossRef]
    [Google Scholar]
  43. Zulianello L., Kaneko K., Scott M., Erpel S., Han D., Cohen F. E., Prusiner S. B. 2000; Dominant-negative inhibition of prion formation diminished by deletion mutagenesis of the prion protein. J Virol 74:4351–4360 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.2008/002303-0
Loading
/content/journal/jgv/10.1099/vir.0.2008/002303-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error