No influence of amyloid--degrading neprilysin activity on prion pathogenesis Free

Abstract

Transmissible spongiform encephalopathies are characterized by the accumulation of PrP, a protease-resistant form of a host-derived protein termed PrP. Substantial evidence indicates that PrP represents an essential component of the infectious agent, which is termed prion. The accumulation of PrP within the central nervous system of prion-infected organisms is a dynamic process that is regulated both by production and by clearance of PrP. Although several proteases have been implicated in proteolysis of PrP, the mechanisms underlying proteolysis of PrP remain unclear. Here, it was investigated whether neprilysin, a metalloprotease known to degrade extracellular amyloidogenic proteins such as amyloid-, plays a role in prion pathogenesis . As neprilysin has a broad substrate specificity and is localized subcellularly in the vicinity of PrP, it represents a plausible candidate for prion degradation. Prions were therefore administered to mice lacking or overexpressing neprilysin in brain. However, the gene dosage of neprilysin did not modulate accumulation of PrP in brain. Also, incubation times and clinical course of prion disease, as well as brain infectivity titres at terminal stage, were unaffected. These data rule out neprilysin as a major modulator of PrP accumulation and prion pathogenesis.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.80811-0
2005-06-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/86/6/vir861861.html?itemId=/content/journal/jgv/10.1099/vir.0.80811-0&mimeType=html&fmt=ahah

References

  1. Aguzzi A., Haass C. 2003; Games played by rogue proteins in prion disorders and Alzheimer's disease. Science 302:814–818 [CrossRef]
    [Google Scholar]
  2. Aguzzi A., Polymenidou M. 2004; Mammalian prion biology: one century of evolving concepts. Cell 116:313–327 [CrossRef]
    [Google Scholar]
  3. Backstrom J. R., Lim G. P., Cullen M. J., Tökés Z. A. 1996; Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid- β peptide (1-40). J Neurosci 16:7910–7919
    [Google Scholar]
  4. Borchelt D. R., Davis J., Fischer M. 8 other authors 1996; A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal 13:159–163 [CrossRef]
    [Google Scholar]
  5. Büeler H., 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 [CrossRef]
    [Google Scholar]
  6. Büeler H., Aguzzi A., Sailer A., Greiner R.-A., Autenried P., Aguet M., Weissmann C. 1993; Mice devoid of PrP are resistant to scrapie. Cell 73:1339–1347 [CrossRef]
    [Google Scholar]
  7. Checler F., Vincent B. 2002; Alzheimer's and prion diseases: distinct pathologies, common proteolytic denominators. Trends Neurosci 25:616–620 [CrossRef]
    [Google Scholar]
  8. Chen S. G., Teplow D. B., Parchi P., Teller J. K., Gambetti P., Autilio-Gambetti L. 1995; Truncated forms of the human prion protein in normal brain and in prion diseases. J Biol Chem 270:19173–19180 [CrossRef]
    [Google Scholar]
  9. Enari M., Flechsig E., Weissmann C. 2001; Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci U S A 98:9295–9299 [CrossRef]
    [Google Scholar]
  10. 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
    [Google Scholar]
  11. Glatzel M., Aguzzi A. 2000; PrPC expression in the peripheral nervous system is a determinant of prion neuroinvasion. J Gen Virol 81:2813–2821
    [Google Scholar]
  12. Glatzel M., Heppner F. L., Albers K. M., Aguzzi A. 2001; Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:25–34 [CrossRef]
    [Google Scholar]
  13. 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 [CrossRef]
    [Google Scholar]
  14. Iwata N., Tsubuki S., Takaki Y. 7 other authors 2001; Metabolic regulation of brain A β by neprilysin. Science 292:1550–1552 [CrossRef]
    [Google Scholar]
  15. Jiménez-Huete A., Lievens P. M. J., Vidal R., Piccardo P., Ghetti B., Tagliavini F., Frangione B., Prelli F. 1998; Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues. Am J Pathol 153:1561–1572 [CrossRef]
    [Google Scholar]
  16. 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 [CrossRef]
    [Google Scholar]
  17. Lu B., Gerard N. P., Kolakowski L. F. Jr, Bozza M., Zurakowski D., Finco O., Carroll M. C., Gerard C. 1995; Neutral endopeptidase modulation of septic shock. J Exp Med 181:2271–2275 [CrossRef]
    [Google Scholar]
  18. Luhr K. M., Nordström E. K., Löw P., Ljunggren H.-G., Taraboulos A., Kristensson K. 2004; Scrapie protein degradation by cysteine proteases in CD11c+ dendritic cells and GT1-1 neuronal cells. J Virol 78:4776–4782 [CrossRef]
    [Google Scholar]
  19. Mohajeri M. H., Kuehnle K., Li H., Poirier R., Tracy J., Nitsch R. M. 2004; Anti-amyloid activity of neprilysin in plaque-bearing mouse models of Alzheimer's disease. FEBS Lett 562:16–21 [CrossRef]
    [Google Scholar]
  20. Prusiner S. B., Cochran S. P., Groth D. F., Downey D. E., Bowman K. A., Martinez H. M. 1982; Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol 11:353–358 [CrossRef]
    [Google Scholar]
  21. Shirotani K., Tsubuki S., Iwata N. 9 other authors 2001; Neprilysin degrades both amyloid β peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem 276:21895–21901 [CrossRef]
    [Google Scholar]
  22. Taraboulos A., Jendroska K., Serban D., Yang S.-L., DeArmond S. J., Prusiner S. B. 1992; Regional mapping of prion proteins in brain. Proc Natl Acad Sci U S A 89:7620–7624 [CrossRef]
    [Google Scholar]
  23. Turner A. J. 2003; Exploring the structure and function of zinc metallopeptidases: old enzymes and new discoveries. Biochem Soc Trans 31:723–727
    [Google Scholar]
  24. Vincent B., Paitel E., Saftig P., Frobert Y., Hartmann D., De Strooper B., Grassi J., Lopez-Perez E., Checler F. 2001; The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein. J Biol Chem 276:37743–37746
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.80811-0
Loading
/content/journal/jgv/10.1099/vir.0.80811-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed