Heparin-like molecules bind differentially to prion-proteins and change their intracellular metabolic fate
Corresponding Author
Ruth Gabizon
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, IsraelSearch for more papers by this authorZeev Meiner
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel
Search for more papers by this authorMichele Halimi
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel
Search for more papers by this authorShmuel A. Ben-Sasson
Department of Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Search for more papers by this authorCorresponding Author
Ruth Gabizon
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, IsraelSearch for more papers by this authorZeev Meiner
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel
Search for more papers by this authorMichele Halimi
Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel
Search for more papers by this authorShmuel A. Ben-Sasson
Department of Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Search for more papers by this authorAbstract
PrPSc is the only known component of the scrapie prion. The difference between PrPSc and its normal isoform PrPc is probably conformational, since no difference has been found in the amino acid sequence or postranslational modifications between both proteins. Heparan sulfate (HS) has been shown to be a component of amyloid plaques in a number of diseases including the prion diseases. We now present evidence that PrP can specifically bind to heparin-like compounds and that this interaction might have a physiological significance. HS can increase the concentration of PrP in normal neuroblastoma cells, whereas low molecular weight heparin (LMWH) does not. In contrast, LMWH and other heparin-like molecules, excluding HS, can inhibit the synthesis of PrPSc in scrapie infected cells and reverse their phenotype back to normal as judged by measurement of PrPSc by immunoblotting and by infectivity experiments. Whether an interaction between PrP and glycosaminoglycans plays a direct role in the conversion of PrPc into PrPSc remains to be established. © 1993 Wiley-Liss, Inc.
References
- Baeuerle, P. A., and Huttner, W. B. (1986) Chlorate—a potent inhibitor of protein sulfation in intact cells. BBRC, 141: 870–877.
- Benezra, M., Vlodavsky, I., Yayon, A., Bar-Shavit, R., Regan, J., Chang, M., and Ben-Sasson, S. A. (1992) Reversal of basic fibroblast growth factor-mediated autocrine cell transformation by aromatic anionic compounds. Cancer Res. 52: 5656–5662.
- Bolton, D. C., McKinley, M. P., and Prusiner, S. B. (1982) Identification with a protein that purifies with the scrapie prion. Science, 218: 1309–1311.
- Butler, D. A., Scott, M. R. D., Bockman, J. M., Borcheldt, D. R., Taraboulus, A., Hsiao, K. K. Kingsbury, D. T., and Prusiner, S. B. (1988) Scrapie infected murine neuroblastoma cells produce protease resistant prion proteins. J. Virol. 62: 1558–1564.
- Caughey, B., and Raymond, G. J. (1993) Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells. J. Virol, 67: 643–650.
- Cowles, E. A., Brauker, J. H., and Anderson, R. L. (1987) Turnover of sulfated glycosamonoglycans in fibroblasts derived from patients with Werner's Syndrome. Exp. Cell Res. 168: 347–357.
- DeArmond, S. J., McKinley, M. P., Barry., R. A., Braunfeld, M. B., McColloch, J. R., and Prusiner, S. B. (1985) Identification of prion amyloid filaments in scrapie infected brains. Cell, 41: 221–235
- Diringer, H. and Ehlers, B. (1991) Chemoprophylaxis of scrapie in mice. J. Gen. Virol. 72: 457–460.
- Ehlers, B. and Diringer, H. (1984) Dextran sulphate 500 delays and prevents mouse scrapie by impairment of agent replication in spleen. J. Gen. Virol. 65: 1325–1330.
- Fransson, L. K. (1987) Structure and function of cell associated proteoglycans. TIBS, 12: 406–411.
- Fransson, L. A., Carlstedt, I., Coster, L., and Malmstrom, A. (1983) Proteoheparan Sulfate from human skin fibroblast. J. Biol. Chem. 97: 14342–14345.
- Hausser, H., and Kresse, H. (1991) Binding of heparin and of the small proteoglycan decorin to the same endocytosis receptor proteins leads to different metabolic consequences. J. Cell Biol. 114: 45–52.
- Hsiao, K., and Prusiner, S. B. (1990) Inherited human prion diseases. Neurology, 40: 1820–1827.
- Hsiao, K., Meiner, Z., Kahana, E., Cass, C., Kahana, I., Avrahami, D., Scarlato, G., Abramsky, O., Prusiner, S. B., and Gabizon, R. (1991) Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease. N. Engl. J. Med. 324: 1091–1097.
- Hsiao, K. K., Scott, M., Foster, D., Groth, D. F., DeArmond, S. J., and Prusiner, S. B. (1990) Spontaneous neurodegeneration in transgenic mice with mutant prion protein of Gerstmann-Straussler syndrome. Science, 250: 1587–1590.
- Jackson, R. L., Busch, S. J., and Cardin, A. D. (1991) Glycosaminoglycans: Molecular properties, protein interactions and role in physiological processes. Physiol. Rev. 71: 481–539.
- Jones, R. T., Walker, J. H., Stadler, H., and Whittaker, V. P. (1982) Further evidence that glycosaminoglycan specific to cholinergic synaptic vesicles recycles during electrical stimulation of the electric organ of Torpedo marmorata. Cell Tissue Res. 224: 685–688.
- Keller, K. M., Brauer, P. R., and Keller, J. M. (1989) Modulation of cell surface heparan sulfate structure by growth of cells in the presence of chlorate. Biochemistry, 28: 8100–8107.
- Kitamoto, T., Tateishi, J., Tashima, I., Takeshita, I., Barry, R. A., DeArmond, S. J., and Prusiner, S. B. (1986) Amyloid plaques in Creutzeldt-Jakob disease stain with prion protein antibodies. Ann. Neurol. 20: 204–208.
- Margolis, R. U., Margolis, R. K., Chang, L. B., and Preti, C. (1975) Glycosaminoglycans of brain during development. Biochemistry, 14: 85–88.
- McKinley, M. P., Bolton, D. C., and Prusiner, S. B. (1983) A protease resistant protein is a structural component of the scrapie prion. Cell, 35: 57–62.
- Meyer, R. K., McKinley, M. P. Bowman, K. A., Branfeld, M. B., Barry, R. A., and Prusiner, S. B. (1986) Separation and properties of cellular and scrapie prion properties. Proc. Natl. Acad. Sci. USA, 83: 2310–2314.
- Neufeld, E. F., and Muenzer, J. (1989) The mucopolysaccharidoses. In: The Metabolic Basis of Inherited Diseases. C. R. Scriver A. L. Beaudet W. S. Sly and D. Valle, eds. McGraw-Hill, New York, 1565–1587.
- Prusiner, S. B. (1991) Molecular biology of prion diseases. Science, 252: 1515–1522.
- Saxena, U., Klein, M. G. and Goldberg, I. J. (1990) Metabolism of endothelial cell-bound lipoprotein lipase. J. Biol. Chem. 265: 12880–12886.
- Saxena, U., Klein, M. G., and Goldberg, I. J. (1991) Transport of lipoprotein lipase across endothelial cells. Proc. Natl. Acad. Sci. USA, 88: 2254–2258.
- Serban, D., Tarabolous, A., DeArmond, S. J., and Prusiner, S. B. (1990) Rapid detection of Creutzfeldt-Jakob Disease and scrapie prion proteins. Neurology, 40: 110–117.
- Snow, A. D., Wight, T. N., Nochlin, D., Koike, Y., Kimata, K., DeArmond, S. J., and Prusiner, S. B. (1990a) Immunolocalization of heparan sulfate proteoglycans to the prion protein amyloid plaques in Gerstmman-Stausller syndrome, Creutzfeldt-Jakob disease and scrapie. Lab. Invest. 63: 601–611.
- Snow, D. A., Mar, H., Nochlin, D., Sekiguchi, R. T., Kimata, K., Koike, Y., and Wight, T. N. (1990b) Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer's disease and Down's Syndrome. Am. J. Pathol. 136: 1253–1270.
- Stahl, N., Borchelt, D. R., Hsiao, K., and Prusiner, S. B. (1987) Glycolipid modification of the scrapie prion protein. Cell, 51: 229–240.
- Stahl, N., Borchelt, D. R., and Prusiner, S. B. (1990) Differential release of cellular and scrapie prion proteins from cellular membranes by phosphatidylinositol-specific phospholipase C. Biochemistry, 29: 5405–5412.
- Taraboulos, A., Serban, D., and Prusiner, S. B. (1990) Scrapie prion proteins accumulate in the cytoplasm of persistently infected cultured cells. J. Cell Biol. 110: 2117–2132.
Citing Literature
