Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells (original) (raw)

Abstract

The accumulation of an abnormal, protease-resistant form of the protein PrP (PrP-res) in hosts with scrapie and related transmissible spongiform encephalopathies appears to be important in disease pathogenesis. To gain insight into the mechanism of PrP-res accumulation and the in vivo antiscrapie activity of certain polyanions, we have studied effects of sulfated glycans on PrP metabolism in scrapie-infected neuroblastoma cells. Pentosan polysulfate, like the amyloid-binding dye Congo red, potently inhibited the accumulation of PrP-res in these cells without apparent effects on the metabolism of the normal isoform. The inhibition was due primarily to prevention of new PrP-res accumulation rather than destabilization of preexisting PrP-res. PrP-res accumulation remained depressed in the cultures after removal of the inhibitors. The activities of other sulfated glycans, nonsulfated polyanions, dextran, and DEAE-dextran were compared with those of pentosan polysulfate and Congo red. This comparison provided evidence that the density of sulfation and molecular size are factors influencing anti-PrP-res activity of sulfated glycans. The relative potencies of these compounds corresponded well with their previously determined antiscrapie activities in vivo, suggesting that the prophylactic effects of sulfated polyanions may be due to inhibition of PrP-res accumulation. Since PrP-res amyloid is known to contain sulfated glycosaminoglycans, we reason that these inhibitors may competitively block an interaction between PrP and endogenous glycosaminoglycans that is essential for its accumulation in a protease-resistant, potentially amyloidogenic state.

643

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aiken J. M., Marsh R. F. The search for scrapie agent nucleic acid. Microbiol Rev. 1990 Sep;54(3):242–246. doi: 10.1128/mr.54.3.242-246.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson N. S., Campbell J. W., Harding M. M., Rees D. A., Samuel J. W. X-ray diffraction studies of polysaccharide sulphates: double helix models for k- and l-carrageenans. J Mol Biol. 1969 Oct 14;45(1):85–99. doi: 10.1016/0022-2836(69)90211-3. [DOI] [PubMed] [Google Scholar]
  3. Baba M., Nakajima M., Schols D., Pauwels R., Balzarini J., De Clercq E. Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro. Antiviral Res. 1988 Sep;9(6):335–343. doi: 10.1016/0166-3542(88)90035-6. [DOI] [PubMed] [Google Scholar]
  4. Bendheim P. E., Barry R. A., DeArmond S. J., Stites D. P., Prusiner S. B. Antibodies to a scrapie prion protein. Nature. 1984 Aug 2;310(5976):418–421. doi: 10.1038/310418a0. [DOI] [PubMed] [Google Scholar]
  5. Biesert L., Suhartono H., Winkler I., Meichsner C., Helsberg M., Hewlett G., Klimetzek V., Mölling K., Schlumberger H. D., Schrinner E. Inhibition of HIV and virus replication by polysulphated polyxylan: HOE/BAY 946, a new antiviral compound. AIDS. 1988 Dec;2(6):449–457. doi: 10.1097/00002030-198812000-00007. [DOI] [PubMed] [Google Scholar]
  6. Bloksma N., de Reuver M. J., Willers J. M. Influence on macrophage functions as a possible basis of immunomodification by polyanions. Ann Immunol (Paris) 1980 Nov-Dec;131D(3):255–265. [PubMed] [Google Scholar]
  7. Bolton D. C., McKinley M. P., Prusiner S. B. Identification of a protein that purifies with the scrapie prion. Science. 1982 Dec 24;218(4579):1309–1311. doi: 10.1126/science.6815801. [DOI] [PubMed] [Google Scholar]
  8. Borchelt D. R., Scott M., Taraboulos A., Stahl N., Prusiner S. B. Scrapie and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells. J Cell Biol. 1990 Mar;110(3):743–752. doi: 10.1083/jcb.110.3.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bradfield J. W., Born G. V. Lymphocytosis produced by heparin and other sulphated polysaccharides in mice and rats. Cell Immunol. 1974 Oct;14(1):22–32. doi: 10.1016/0008-8749(74)90165-8. [DOI] [PubMed] [Google Scholar]
  10. Brown P., Coker-Vann M., Pomeroy K., Franko M., Asher D. M., Gibbs C. J., Jr, Gajdusek D. C. Diagnosis of Creutzfeldt-Jakob disease by Western blot identification of marker protein in human brain tissue. N Engl J Med. 1986 Feb 27;314(9):547–551. doi: 10.1056/NEJM198602273140904. [DOI] [PubMed] [Google Scholar]
  11. Bruce M. E., McBride P. A., Farquhar C. F. Precise targeting of the pathology of the sialoglycoprotein, PrP, and vacuolar degeneration in mouse scrapie. Neurosci Lett. 1989 Jul 17;102(1):1–6. doi: 10.1016/0304-3940(89)90298-x. [DOI] [PubMed] [Google Scholar]
  12. Carlson G. A., Kingsbury D. T., Goodman P. A., Coleman S., Marshall S. T., DeArmond S., Westaway D., Prusiner S. B. Linkage of prion protein and scrapie incubation time genes. Cell. 1986 Aug 15;46(4):503–511. doi: 10.1016/0092-8674(86)90875-5. [DOI] [PubMed] [Google Scholar]
  13. Caughey B. W., Dong A., Bhat K. S., Ernst D., Hayes S. F., Caughey W. S. Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy. Biochemistry. 1991 Aug 6;30(31):7672–7680. doi: 10.1021/bi00245a003. [DOI] [PubMed] [Google Scholar]
  14. Caughey B., Race R. E. Potent inhibition of scrapie-associated PrP accumulation by congo red. J Neurochem. 1992 Aug;59(2):768–771. doi: 10.1111/j.1471-4159.1992.tb09437.x. [DOI] [PubMed] [Google Scholar]
  15. Caughey B., Raymond G. J., Ernst D., Race R. E. 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. 1991 Dec;65(12):6597–6603. doi: 10.1128/jvi.65.12.6597-6603.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Caughey B., Raymond G. J. The scrapie-associated form of PrP is made from a cell surface precursor that is both protease- and phospholipase-sensitive. J Biol Chem. 1991 Sep 25;266(27):18217–18223. [PubMed] [Google Scholar]
  17. Chesebro B., Race R., Wehrly K., Nishio J., Bloom M., Lechner D., Bergstrom S., Robbins K., Mayer L., Keith J. M. Identification of scrapie prion protein-specific mRNA in scrapie-infected and uninfected brain. Nature. 1985 May 23;315(6017):331–333. doi: 10.1038/315331a0. [DOI] [PubMed] [Google Scholar]
  18. Czub M., Braig H. R., Diringer H. Replication of the scrapie agent in hamsters infected intracerebrally confirms the pathogenesis of an amyloid-inducing virosis. J Gen Virol. 1988 Jul;69(Pt 7):1753–1756. doi: 10.1099/0022-1317-69-7-1753. [DOI] [PubMed] [Google Scholar]
  19. DeArmond S. J., Mobley W. C., DeMott D. L., Barry R. A., Beckstead J. H., Prusiner S. B. Changes in the localization of brain prion proteins during scrapie infection. Neurology. 1987 Aug;37(8):1271–1280. doi: 10.1212/wnl.37.8.1271. [DOI] [PubMed] [Google Scholar]
  20. Diamantstein T., Wagner B., Beyse I., Odenwald M. V., Schulz G. Stimulation of humoral antibody formation by polyanions. II. The influence of sulfate esters of polymers on the immune response in mice. Eur J Immunol. 1971 Nov;1(5):340–343. doi: 10.1002/eji.1830010507. [DOI] [PubMed] [Google Scholar]
  21. Diedrich J. F., Bendheim P. E., Kim Y. S., Carp R. I., Haase A. T. Scrapie-associated prion protein accumulates in astrocytes during scrapie infection. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):375–379. doi: 10.1073/pnas.88.2.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Diringer H., Ehlers B. Chemoprophylaxis of scrapie in mice. J Gen Virol. 1991 Feb;72(Pt 2):457–460. doi: 10.1099/0022-1317-72-2-457. [DOI] [PubMed] [Google Scholar]
  23. Diringer H., Gelderblom H., Hilmert H., Ozel M., Edelbluth C., Kimberlin R. H. Scrapie infectivity, fibrils and low molecular weight protein. Nature. 1983 Dec 1;306(5942):476–478. doi: 10.1038/306476a0. [DOI] [PubMed] [Google Scholar]
  24. Doh-ura K., Tateishi J., Sasaki H., Kitamoto T., Sakaki Y. Pro----leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Sträussler syndrome. Biochem Biophys Res Commun. 1989 Sep 15;163(2):974–979. doi: 10.1016/0006-291x(89)92317-6. [DOI] [PubMed] [Google Scholar]
  25. Dörries R., Schimpl A., Wecker E. Action of dextran sulfate as a direct and general B cell mitogen. Eur J Immunol. 1974 Mar;4(3):230–233. doi: 10.1002/eji.1830040315. [DOI] [PubMed] [Google Scholar]
  26. Ehlers B., Diringer H. Dextran sulphate 500 delays and prevents mouse scrapie by impairment of agent replication in spleen. J Gen Virol. 1984 Aug;65(Pt 8):1325–1330. doi: 10.1099/0022-1317-65-8-1325. [DOI] [PubMed] [Google Scholar]
  27. Ehlers B., Rudolph R., Diringer H. The reticuloendothelial system in scrapie pathogenesis. J Gen Virol. 1984 Feb;65(Pt 2):423–428. doi: 10.1099/0022-1317-65-2-423. [DOI] [PubMed] [Google Scholar]
  28. Farquhar C. F., Dickinson A. G. Prolongation of scrapie incubation period by an injection of dextran sulphate 500 within the month before or after infection. J Gen Virol. 1986 Mar;67(Pt 3):463–473. doi: 10.1099/0022-1317-67-3-463. [DOI] [PubMed] [Google Scholar]
  29. Glenner G. G. Amyloid deposits and amyloidosis: the beta-fibrilloses (second of two parts). N Engl J Med. 1980 Jun 12;302(24):1333–1343. doi: 10.1056/NEJM198006123022403. [DOI] [PubMed] [Google Scholar]
  30. Goldgaber D., Goldfarb L. G., Brown P., Asher D. M., Brown W. T., Lin S., Teener J. W., Feinstone S. M., Rubenstein R., Kascsak R. J. Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker's syndrome. Exp Neurol. 1989 Nov;106(2):204–206. doi: 10.1016/0014-4886(89)90095-2. [DOI] [PubMed] [Google Scholar]
  31. Goldmann W., Hunter N., Foster J. D., Salbaum J. M., Beyreuther K., Hope J. Two alleles of a neural protein gene linked to scrapie in sheep. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2476–2480. doi: 10.1073/pnas.87.7.2476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hart P. D., Young M. R. Interference with normal phagosome-lysosome fusion in macrophages, using ingested yeast cells and suramin. Nature. 1975 Jul 3;256(5512):47–49. doi: 10.1038/256047a0. [DOI] [PubMed] [Google Scholar]
  33. Henner D. J., Yang M., Chen E., Hellmiss R., Rodriguez H., Low M. G. Sequence of the Bacillus thuringiensis phosphatidylinositol specific phospholipase C. Nucleic Acids Res. 1988 Nov 11;16(21):10383–10383. doi: 10.1093/nar/16.21.10383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hope J., Reekie L. J., Hunter N., Multhaup G., Beyreuther K., White H., Scott A. C., Stack M. J., Dawson M., Wells G. A. Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature. 1988 Nov 24;336(6197):390–392. doi: 10.1038/336390a0. [DOI] [PubMed] [Google Scholar]
  35. Hsiao K. K., Scott M., Foster D., Groth D. F., DeArmond S. J., Prusiner S. B. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science. 1990 Dec 14;250(4987):1587–1590. doi: 10.1126/science.1980379. [DOI] [PubMed] [Google Scholar]
  36. Hsiao K., Baker H. F., Crow T. J., Poulter M., Owen F., Terwilliger J. D., Westaway D., Ott J., Prusiner S. B. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature. 1989 Mar 23;338(6213):342–345. doi: 10.1038/338342a0. [DOI] [PubMed] [Google Scholar]
  37. Hunter N., Hope J., McConnell I., Dickinson A. G. Linkage of the scrapie-associated fibril protein (PrP) gene and Sinc using congenic mice and restriction fragment length polymorphism analysis. J Gen Virol. 1987 Oct;68(Pt 10):2711–2716. doi: 10.1099/0022-1317-68-10-2711. [DOI] [PubMed] [Google Scholar]
  38. Kimberlin R. H., Walker C. A. Suppression of scrapie infection in mice by heteropolyanion 23, dextran sulfate, and some other polyanions. Antimicrob Agents Chemother. 1986 Sep;30(3):409–413. doi: 10.1128/aac.30.3.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kimberlin R. H., Walker C. A. The antiviral compound HPA-23 can prevent scrapie when administered at the time of infection. Arch Virol. 1983;78(1-2):9–18. doi: 10.1007/BF01310854. [DOI] [PubMed] [Google Scholar]
  40. Kisilevsky R. From arthritis to Alzheimer's disease: current concepts on the pathogenesis of amyloidosis. Can J Physiol Pharmacol. 1987 Sep;65(9):1805–1815. doi: 10.1139/y87-282. [DOI] [PubMed] [Google Scholar]
  41. Ladogana A., Casaccia P., Ingrosso L., Cibati M., Salvatore M., Xi Y. G., Masullo C., Pocchiari M. Sulphate polyanions prolong the incubation period of scrapie-infected hamsters. J Gen Virol. 1992 Mar;73(Pt 3):661–665. doi: 10.1099/0022-1317-73-3-661. [DOI] [PubMed] [Google Scholar]
  42. Low M. G., Stiernberg J., Waneck G. L., Flavell R. A., Kincade P. W. Cell-specific heterogeneity in sensitivity of phosphatidylinositol-anchored membrane antigens to release by phospholipase C. J Immunol Methods. 1988 Oct 4;113(1):101–111. doi: 10.1016/0022-1759(88)90386-9. [DOI] [PubMed] [Google Scholar]
  43. McCarthy R. E., Arnold L. W., Babcock G. F. Dextran sulphate: an adjuvant for cell-mediated immune responses. Immunology. 1977 Jun;32(6):963–974. [PMC free article] [PubMed] [Google Scholar]
  44. McKinley M. P., Taraboulos A., Kenaga L., Serban D., Stieber A., DeArmond S. J., Prusiner S. B., Gonatas N. Ultrastructural localization of scrapie prion proteins in cytoplasmic vesicles of infected cultured cells. Lab Invest. 1991 Dec;65(6):622–630. [PubMed] [Google Scholar]
  45. Moelling K., Schulze T., Diringer H. Inhibition of human immunodeficiency virus type 1 RNase H by sulfated polyanions. J Virol. 1989 Dec;63(12):5489–5491. doi: 10.1128/jvi.63.12.5489-5491.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Narindrasorasak S., Lowery D., Gonzalez-DeWhitt P., Poorman R. A., Greenberg B., Kisilevsky R. High affinity interactions between the Alzheimer's beta-amyloid precursor proteins and the basement membrane form of heparan sulfate proteoglycan. J Biol Chem. 1991 Jul 15;266(20):12878–12883. [PubMed] [Google Scholar]
  47. Pocchiari M., Salvatore M., Ladogana A., Ingrosso L., Xi Y. G., Cibati M., Masullo C. Experimental drug treatment of scrapie: a pathogenetic basis for rationale therapeutics. Eur J Epidemiol. 1991 Sep;7(5):556–561. doi: 10.1007/BF00143139. [DOI] [PubMed] [Google Scholar]
  48. Prusiner S. B., McKinley M. P., Bowman K. A., Bolton D. C., Bendheim P. E., Groth D. F., Glenner G. G. Scrapie prions aggregate to form amyloid-like birefringent rods. Cell. 1983 Dec;35(2 Pt 1):349–358. doi: 10.1016/0092-8674(83)90168-x. [DOI] [PubMed] [Google Scholar]
  49. Prusiner S. B. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515–1522. doi: 10.1126/science.1675487. [DOI] [PubMed] [Google Scholar]
  50. Race R. E., Caughey B., Graham K., Ernst D., Chesebro B. Analyses of frequency of infection, specific infectivity, and prion protein biosynthesis in scrapie-infected neuroblastoma cell clones. J Virol. 1988 Aug;62(8):2845–2849. doi: 10.1128/jvi.62.8.2845-2849.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Race R. E., Fadness L. H., Chesebro B. Characterization of scrapie infection in mouse neuroblastoma cells. J Gen Virol. 1987 May;68(Pt 5):1391–1399. doi: 10.1099/0022-1317-68-5-1391. [DOI] [PubMed] [Google Scholar]
  52. Race R. E., Graham K., Ernst D., Caughey B., Chesebro B. Analysis of linkage between scrapie incubation period and the prion protein gene in mice. J Gen Virol. 1990 Feb;71(Pt 2):493–497. doi: 10.1099/0022-1317-71-2-493. [DOI] [PubMed] [Google Scholar]
  53. Rohwer R. G. The scrapie agent: "a virus by any other name". Curr Top Microbiol Immunol. 1991;172:195–232. [PubMed] [Google Scholar]
  54. Ruoslahti E. Structure and biology of proteoglycans. Annu Rev Cell Biol. 1988;4:229–255. doi: 10.1146/annurev.cb.04.110188.001305. [DOI] [PubMed] [Google Scholar]
  55. Snow A. D., Kisilevsky R., Willmer J., Prusiner S. B., DeArmond S. J. Sulfated glycosaminoglycans in amyloid plaques of prion diseases. Acta Neuropathol. 1989;77(4):337–342. doi: 10.1007/BF00687367. [DOI] [PubMed] [Google Scholar]
  56. Snow A. D., Wight T. N., Nochlin D., Koike Y., Kimata K., DeArmond S. J., Prusiner S. B. Immunolocalization of heparan sulfate proteoglycans to the prion protein amyloid plaques of Gerstmann-Straussler syndrome, Creutzfeldt-Jakob disease and scrapie. Lab Invest. 1990 Nov;63(5):601–611. [PubMed] [Google Scholar]
  57. TAKEMOTO K. K., FABISCH P. INHIBITION OF HERPES VIRUS BY NATURAL AND SYNTHETIC ACID POLYSACCHARIDES. Proc Soc Exp Biol Med. 1964 May;116:140–144. doi: 10.3181/00379727-116-29183. [DOI] [PubMed] [Google Scholar]
  58. Vogt W., Rühl H., Wagner B., Diamantstein T. Stimulation of DNA synthesis in mouse lymphoid cells by polyanions in vitro. II. Relationship between adjuvant activity and stimulation of DNA synthesis by polyanions. Eur J Immunol. 1973 Aug;3(8):493–496. doi: 10.1002/eji.1830030808. [DOI] [PubMed] [Google Scholar]
  59. Woody A. Y., Reisbig R. R., Woody R. W. Spectroscopic studies of Congo Red binding to RNA polymerase. Biochim Biophys Acta. 1981 Aug 27;655(1):82–88. doi: 10.1016/0005-2787(81)90069-1. [DOI] [PubMed] [Google Scholar]
  60. WuDunn D., Spear P. G. Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol. 1989 Jan;63(1):52–58. doi: 10.1128/jvi.63.1.52-58.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Xi Y. G., Ingrosso L., Ladogana A., Masullo C., Pocchiari M. Amphotericin B treatment dissociates in vivo replication of the scrapie agent from PrP accumulation. Nature. 1992 Apr 16;356(6370):598–601. doi: 10.1038/356598a0. [DOI] [PubMed] [Google Scholar]