Skip to content
1887

Journal of General Virology header logo Journal of General Virology

Volume 94, Issue 2

Protease-sensitive prion species in neoplastic spleens of prion-infected mice with uncoupling of PrP and prion infectivity No Access

Abstract

Prion diseases are fatal neurodegenerative disorders. An important step in disease pathophysiology is the conversion of cellular prion protein (PrP) to disease-associated misfolded conformers (PrP). These misfolded PrP variants are a common component of prion infectivity and are detectable in diseased brain and lymphoreticular organs such as spleen. In the latter, PrP is thought to replicate mainly in follicular dendritic cells within spleen follicles. Although the presence of PrP is a hallmark for prion disease and serves as a main diagnostic criterion, in certain instances the amount of PrP does not correlate well with neurotoxicity or prion infectivity. Therefore, it has been proposed that prions might be a mixture of different conformers and aggregates with differing properties. This study investigated the impact of disruption of spleen architecture by neoplasia on the abundance of different PrP species in spleens of prion-infected mice. Although follicular integrity was completely disturbed, titres of prion infectivity in neoplastic spleens were not significantly altered, yet no protease-resistant PrP was detectable. Instead, unique protease-sensitive prion species could be detected in neoplastic spleens. These results indicate the dissociation of PrP and prion infectivity and showed the presence of non-PrP PrP species in spleen with divergent biochemical properties that become apparent after tissue architecture disruption.

  • Received:
  • Accepted:
  • Published Online:
© 2013 SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.045922-0
2013-02-01
2025-03-20
Loading full text...

Full text loading...

References

  1. Aguzzi A. 1997; Neuro-immune connection in spread of prions in the body?. Lancet 349:742–743 [View Article][PubMed]
     [Google Scholar]
  2. Aguzzi A. 2003; Prions and the immune system: a journey through gut, spleen, and nerves. Adv Immunol 81:123–171 [View Article][PubMed]
     [Google Scholar]
  3. Aguzzi A. 2004; Understanding the diversity of prions. Nat Cell Biol 6:290–292 [View Article][PubMed]
     [Google Scholar]
  4. Aguzzi A., Rajendran L. 2009; The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64:783–790 [View Article][PubMed]
     [Google Scholar]
  5. Barria M. A., Mukherjee A., Gonzalez-Romero D., Morales R., Soto C. 2009; De novo generation of infectious prions in vitro produces a new disease phenotype. PLoS Pathog 5:e1000421 [View Article][PubMed]
     [Google Scholar]
  6. 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 [View Article][PubMed]
     [Google Scholar]
  7. Blättler T., Brandner S., Raeber A. J., Klein M. A., Voigtländer T., Weissmann C., Aguzzi A. 1997; PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389:69–73 [View Article][PubMed]
     [Google Scholar]
  8. Bolton D. C., McKinley M. P., Prusiner S. B. 1982; Identification of a protein that purifies with the scrapie prion. Science 218:1309–1311 [View Article][PubMed]
     [Google Scholar]
  9. Brown K. L., Stewart K., Ritchie D. L., Mabbott N. A., Williams A., Fraser H., Morrison W. I., Bruce M. E. 1999; Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat Med 5:1308–1312 [View Article][PubMed]
     [Google Scholar]
  10. Brown K. L., Stewart K., Ritchie D., Fraser H., Morrison W. I., Bruce M. E. 2000; Follicular dendritic cells in scrapie pathogenesis. Arch Virol Suppl 16:13–21[PubMed]
     [Google Scholar]
  11. Büeler H. R., Fischer M., Lang Y., Bluethmann H., Lipp H. P., DeArmond S. J., Prusiner S. B., Aguet M., Weissmann C. 1992; Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356:577–582 [View Article][PubMed]
     [Google Scholar]
  12. Castro-Seoane R., Hummerich H., Sweeting T., Tattum M. H., Linehan J. M., Fernandez de Marco M., Brandner S., Collinge J., Klöhn P. C. 2012; Plasmacytoid dendritic cells sequester high prion titres at early stages of prion infection. PLoS Pathog 8:e1002538 [View Article][PubMed]
     [Google Scholar]
  13. Caughey B., Raymond G. J., Ernst D., Race R. E. 1991; N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state. J Virol 65:6597–6603[PubMed]
     [Google Scholar]
  14. Cronier S., Gros N., Tattum M. H., Jackson G. S., Clarke A. R., Collinge J., Wadsworth J. D. 2008; Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin. Biochem J 416:297–305 [View Article][PubMed]
     [Google Scholar]
  15. Fischer M., Rülicke T., Raeber A., Sailer A., Moser M., Oesch B., Brandner S., Aguzzi A., Weissmann C. 1996; Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15:1255–1264[PubMed]
     [Google Scholar]
  16. Gambetti P., Dong Z., Yuan J., Xiao X., Zheng M., Alshekhlee A., Castellani R., Cohen M., Barria M. A. other authors 2008; A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol 63:697–708 [View Article][PubMed]
     [Google Scholar]
  17. Ganor Y., Grinberg I., Reis A., Cooper I., Goldstein R. S., Levite M. 2009; Human T-leukemia and T-lymphoma express glutamate receptor AMPA GluR3, and the neurotransmitter glutamate elevates the cancer-related matrix-metalloproteinases inducer CD147/EMMPRIN, MMP-9 secretion and engraftment of T-leukemia in vivo . Leuk Lymphoma 50:985–997 [View Article][PubMed]
     [Google Scholar]
  18. Geissen M., Krasemann S., Matschke J., Glatzel M. 2007; Understanding the natural variability of prion diseases. Vaccine 25:5631–5636 [View Article][PubMed]
     [Google Scholar]
  19. Glatzel M., Aguzzi A. 2000; PrPC expression in the peripheral nervous system is a determinant of prion neuroinvasion. J Gen Virol 81:2813–2821[PubMed]
     [Google Scholar]
  20. Glatzel M., Aguzzi A. 2001; Sympathetic prions. ScientificWorldJournal 1:555–556 [View Article][PubMed]
     [Google Scholar]
  21. Glatzel M., Abela E., Maissen M., Aguzzi A. 2003; Extraneural pathologic prion protein in sporadic Creutzfeldt–Jakob disease. N Engl J Med 349:1812–1820 [View Article][PubMed]
     [Google Scholar]
  22. Glatzel M., Stoeck K., Seeger H., Lührs T., Aguzzi A. 2005; Human prion diseases: molecular and clinical aspects. Arch Neurol 62:545–552 [View Article][PubMed]
     [Google Scholar]
  23. González L., Thorne L., Jeffrey M., Martin S., Spiropoulos J., Beck K. E., Lockey R. W., Vickery C. M., Holder T., Terry L. 2012; Infectious titres of sheep scrapie and bovine spongiform encephalopathy agents cannot be accurately predicted from quantitative laboratory test results. J Gen Virol 93:2518–2527 [View Article][PubMed]
     [Google Scholar]
  24. Harbers K., Schnieke A., Stuhlmann H., Jähner D., Jaenisch R. 1981; DNA methylation and gene expression: endogenous retroviral genome becomes infectious after molecular cloning. Proc Natl Acad Sci U S A 78:7609–7613 [View Article][PubMed]
     [Google Scholar]
  25. Hoffmann C., Eiden M., Kaatz M., Keller M., Ziegler U., Rogers R., Hills B., Balkema-Buschmann A., van Keulen L. other authors 2011; BSE infectivity in jejunum, ileum and ileocaecal junction of incubating cattle. Vet Res 42:21 [View Article][PubMed]
     [Google Scholar]
  26. Horiuchi M., Caughey B. 1999; Specific binding of normal prion protein to the scrapie form via a localized domain initiates its conversion to the protease-resistant state. EMBO J 18:3193–3203 [View Article][PubMed]
     [Google Scholar]
  27. Hsiao K. K., Groth D., Scott M., Yang S. L., Serban H., Rapp D., Foster D., Torchia M., Dearmond S. J., Prusiner S. B. 1994; Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci U S A 91:9126–9130 [View Article][PubMed]
     [Google Scholar]
  28. Jeffrey M., González L. 2004; Pathology and pathogenesis of bovine spongiform encephalopathy and scrapie. Curr Top Microbiol Immunol 284:65–97[PubMed]
     [Google Scholar]
  29. Jeffrey M., McGovern G., Goodsir C. M., Brown K. L., Bruce M. E. 2000; Sites of prion protein accumulation in scrapie-infected mouse spleen revealed by immuno-electron microscopy. J Pathol 191:323–332 [View Article][PubMed]
     [Google Scholar]
  30. Jewell J. E., Brown J., Kreeger T., Williams E. S. 2006; Prion protein in cardiac muscle of elk (Cervus elaphus nelsoni) and white-tailed deer (Odocoileus virginianus) infected with chronic wasting disease. J Gen Virol 87:3443–3450 [View Article][PubMed]
     [Google Scholar]
  31. Kaeser P. S., Klein M. A., Schwarz P., Aguzzi A. 2001; Efficient lymphoreticular prion propagation requires PrPc in stromal and hematopoietic cells. J Virol 75:7097–7106 [View Article][PubMed]
     [Google Scholar]
  32. Kimberlin R. H., Walker C. A. 1989; The role of the spleen in the neuroinvasion of scrapie in mice. Virus Res 12:201–211 [View Article][PubMed]
     [Google Scholar]
  33. Klöhn P. C., Stoltze L., Flechsig E., Enari M., Weissmann C. 2003; A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc Natl Acad Sci U S A 100:11666–11671 [View Article][PubMed]
     [Google Scholar]
  34. Kranich J., Krautler N. J., Heinen E., Polymenidou M., Bridel C., Schildknecht A., Huber C., Kosco-Vilbois M. H., Zinkernagel R. other authors 2008; Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8. J Exp Med 205:1293–1302 [View Article][PubMed]
     [Google Scholar]
  35. Krasemann S., Neumann M., Luepke J. P., Grashorn J., Wurr S., Stocking C., Glatzel M. 2012; Persistent retroviral infection with MoMuLV influences neuropathological signature and phenotype of prion disease. Acta Neuropathol 124:111–126 [View Article][PubMed]
     [Google Scholar]
  36. Lasmézas C. I., Deslys J. P., Robain O., Jaegly A., Beringue V., Peyrin J. M., Fournier J. G., Hauw J. J., Rossier J., Dormont D. 1997; Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275:402–404 [View Article][PubMed]
     [Google Scholar]
  37. Lewis V., Haigh C. L., Masters C. L., Hill A. F., Lawson V. A., Collins S. J. 2012; Prion subcellular fractionation reveals infectivity spectrum, with a high titre–low PrPres level disparity. Mol Neurodegener 7:18 [View Article][PubMed]
     [Google Scholar]
  38. Mabbott N. A., Bruce M. E., Botto M., Walport M. J., Pepys M. B. 2001; Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 7:485–487 [View Article][PubMed]
     [Google Scholar]
  39. Mahal S. P., Baker C. A., Demczyk C. A., Smith E. W., Julius C., Weissmann C. 2007; Prion strain discrimination in cell culture: the cell panel assay. Proc Natl Acad Sci U S A 104:20908–20913 [View Article][PubMed]
     [Google Scholar]
  40. Manson J. C., Jamieson E., Baybutt H., Tuzi N. L., Barron R., McConnell I., Somerville R., Ironside J., Will R. other authors 1999; A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. EMBO J 18:6855–6864 [View Article][PubMed]
     [Google Scholar]
  41. McCulloch L., Brown K. L., Bradford B. M., Hopkins J., Bailey M., Rajewsky K., Manson J. C., Mabbott N. A. 2011; Follicular dendritic cell-specific prion protein (PrP) expression alone is sufficient to sustain prion infection in the spleen. PLoS Pathog 7:e1002402 [View Article][PubMed]
     [Google Scholar]
  42. Montrasio F., Frigg R., Glatzel M., Klein M. A., Mackay F., Aguzzi A., Weissmann C. 2000; Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288:1257–1259 [View Article][PubMed]
     [Google Scholar]
  43. Oesch B., Westaway D., Wälchli M., McKinley M. P., Kent S. B., Aebersold R., Barry R. A., Tempst P., Teplow D. B. other authors 1985; A cellular gene encodes scrapie PrP 27–30 protein. Cell 40:735–746 [View Article][PubMed]
     [Google Scholar]
  44. Owen J. L., Torroella-Kouri M., Iragavarapu-Charyulu V. 2008; Molecular events involved in the increased expression of matrix metalloproteinase-9 by T lymphocytes of mammary tumor-bearing mice. Int J Mol Med 21:125–134[PubMed]
     [Google Scholar]
  45. Piccardo P., Manson J. C., King D., Ghetti B., Barron R. M. 2007; Accumulation of prion protein in the brain that is not associated with transmissible disease. Proc Natl Acad Sci U S A 104:4712–4717 [View Article][PubMed]
     [Google Scholar]
  46. Polymenidou M., Moos R., Scott M., Sigurdson C., Shi Y. Z., Yajima B., Hafner-Bratkovic I., Jerala R., Hornemann S. other authors 2008; The POM monoclonals: a comprehensive set of antibodies to non-overlapping prion protein epitopes. PLoS ONE 3:e3872 [View Article][PubMed]
     [Google Scholar]
  47. Prinz M., Heikenwalder M., Junt T., Schwarz P., Glatzel M., Heppner F. L., Fu Y.-X., Lipp M., Aguzzi A. 2003a; Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425:957–962 [View Article][PubMed]
     [Google Scholar]
  48. Prinz M., Heikenwalder M., Schwarz P., Takeda K., Akira S., Aguzzi A. 2003b; Prion pathogenesis in the absence of Toll-like receptor signalling. EMBO Rep 4:195–199 [View Article][PubMed]
     [Google Scholar]
  49. Prusiner S. B. 1982; Novel proteinaceous infectious particles cause scrapie. Science 216:136–144 [View Article][PubMed]
     [Google Scholar]
  50. Prusiner S. B. 1998; Prions. Proc Natl Acad Sci U S A 95:13363–13383 [View Article][PubMed]
     [Google Scholar]
  51. Qi X., Moore R. A., McGuirl M. A. 2012; Dissociation of recombinant prion protein fibrils into short protofilaments: implications for the endocytic pathway and involvement of the N-terminal domain. Biochemistry 51:4600–4608 [View Article][PubMed]
     [Google Scholar]
  52. Race R. E., Ernst D. 1992; Detection of proteinase K-resistant prion protein and infectivity in mouse spleen by 2 weeks after scrapie agent inoculation. J Gen Virol 73:3319–3323 [View Article][PubMed]
     [Google Scholar]
  53. Rodenburg M., Fischer M., Engelmann A., Harbers S. O., Ziegler M., Löhler J., Stocking C. 2007; Importance of receptor usage, Fli1 activation, and mouse strain for the stem cell specificity of 10A1 murine leukemia virus leukemogenicity. J Virol 81:732–742 [View Article][PubMed]
     [Google Scholar]
  54. Rosenberg N., Jolicoeur P. 1997; Retroviral pathogenesis. In Retroviruses pp. 475–585. Edited by Coffin J. M., Hughes S. H., Varmus H. E. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press;
     [Google Scholar]
  55. 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 [View Article][PubMed]
     [Google Scholar]
  56. Sajnani G., Silva C. J., Ramos A., Pastrana M. A., Onisko B. C., Erickson M. L., Antaki E. M., Dynin I., Vázquez-Fernández E. other authors 2012; PK-sensitive PrP is infectious and shares basic structural features with PK-resistant PrP. PLoS Pathog 8:e1002547 [View Article][PubMed]
     [Google Scholar]
  57. Sakaguchi S., Katamine S., Yamanouchi K., Kishikawa M., Moriuchi R., Yasukawa N., Doi T., Miyamoto T. 1993; Kinetics of infectivity are dissociated from PrP accumulation in salivary glands of Creutzfeldt–Jakob disease agent-inoculated mice. J Gen Virol 74:2117–2123 [View Article][PubMed]
     [Google Scholar]
  58. Sandberg M. K., Al-Doujaily H., Sharps B., Clarke A. R., Collinge J. 2011; Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470:540–542 [View Article][PubMed]
     [Google Scholar]
  59. Schoch G., Seeger H., Bogousslavsky J., Tolnay M., Janzer R. C., Aguzzi A., Glatzel M. 2006; Analysis of prion strains by PrPSc profiling in sporadic Creutzfeldt–Jakob disease. PLoS Med 3:e14 [View Article][PubMed]
     [Google Scholar]
  60. Schwieger M., Löhler J., Friel J., Scheller M., Horak I., Stocking C. 2002; AML1-ETO inhibits maturation of multiple lymphohematopoietic lineages and induces myeloblast transformation in synergy with ICSBP deficiency. J Exp Med 196:1227–1240 [View Article][PubMed]
     [Google Scholar]
  61. Silveira J. R., Raymond G. J., Hughson A. G., Race R. E., Sim V. L., Hayes S. F., Caughey B. 2005; The most infectious prion protein particles. Nature 437:257–261 [View Article][PubMed]
     [Google Scholar]
  62. Supattapone S. 2004; Prion protein conversion in vitro. J Mol Med (Berl) 82:348–356 [View Article][PubMed]
     [Google Scholar]
  63. Thackray A. M., Hopkins L., Bujdoso R. 2007; Proteinase K-sensitive disease-associated ovine prion protein revealed by conformation-dependent immunoassay. Biochem J 401:475–483 [View Article][PubMed]
     [Google Scholar]
  64. Tzaban S., Friedlander G., Schonberger O., Horonchik L., Yedidia Y., Shaked G., Gabizon R., Taraboulos A. 2002; Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes. Biochemistry 41:12868–12875 [View Article][PubMed]
     [Google Scholar]
  65. Urayama A., Morales R., Niehoff M. L., Banks W. A., Soto C. 2011; Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake. FASEB J 25:2792–2803 [View Article][PubMed]
     [Google Scholar]
  66. Wadsworth J. D. F., Joiner S., Hill A. F., Campbell T. A., Desbruslais M., Luthert P. J., Collinge J. 2001; Tissue distribution of protease resistant prion protein in variant Creutzfeldt–Jakob disease using a highly sensitive immunoblotting assay. Lancet 358:171–180 [View Article][PubMed]
     [Google Scholar]
  67. Zabel M. D., Heikenwalder M., Prinz M., Arrighi I., Schwarz P., Kranich J., von Teichman A., Haas K. M., Zeller N. other authors 2007; Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. J Immunol 179:6144–6152[PubMed] [CrossRef]
     [Google Scholar]
/content/journal/jgv/10.1099/vir.0.045922-0
Loading
Protease-sensitive prion species in neoplastic spleens of prion-infected mice with uncoupling of PrPSc and prion infectivity
J. Gen. Virol. 94, 453 (2013); https://doi.org/10.1099/vir.0.045922-0
/content/journal/jgv/10.1099/vir.0.045922-0
/content/journal/jgv/10.1099/vir.0.045922-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

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