Abstract
Enzyme replacement therapy has been shown to be particularly effective for patients with type 1 (non-neuronopathic) Gaucher disease. However, intravenously administered glucocerebrosidase does not reverse or halt the progression of brain damage in patients with type 2 (acute neuronopathic) Gaucher disease. A previous investigation revealed that intracerebral infusion of mannose-terminal glucocerebrosidase was safe in experimental animals. The enzyme had a comparatively long half-life in the brain. It was transported by convection from the site of infusion along white matter fiber tracts to the cerebral cortex where it was endocytosed by neurons. In anticipation of intracerebral administration of mannose-terminal glucocerebrosidase to patients with type 2 Gaucher disease, it was important to learn the mechanism involved in its cellular uptake. We therefore compared the endocytosis of this enzyme by J774 macrophage cells with that in two human neuronal cell lines and a human astrocyte cell line. Mannose-terminal glucocerebrosidase was taken up by cholinergic LA-N-2 cells, but to a much lower extent than by macrophages. Considerably less of the enzyme was endocytosed by dopaminergic SH-SY5Y cells. It was not taken up by NHA astrocytes. The findings provide encouragement for an exploration of intracerebral administration of glucocerebrosidase in patients with type 2 Gaucher disease.
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REFERENCES
Brady, R. O., Kanfer, J. N., and Shapiro, D. 1965. Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher's disease. Biochem. Biophys. Res. Commun. 18:221–225.
Barton, N. W., Brady, R. O., Dambrosia, J. M., Di Bisceglie, A. M., Doppelt, S. H., Hill, S. C., Mankin, H. J., Murray, G. J., Parker, R. I., Argoff, C. E., and et al. 1991. Replacement therapy for inherited enzyme deficiency-macrophage-targeted glucocerebrosidase for Gaucher's disease. N. Engl. J. Med. 324:1464–1470.
Erikson, A., Johansson, K., Mansson, J. E., and Svennerholm, L. 1993. Enzyme replacement therapy of infantile Gaucher disease. Neuropediatrics 24:237–238.
Prows, C. A., Sanchez, N., Daugherty, C., and Grabowski, G. A. 1997. Gaucher disease: enzyme therapy in the acute neuronopathic variant. Am. J. Med. Genet. 71:16–21.
Schiffmann, R., Heyes, M. P., Aerts, J. M., Dambrosia, J. M., Patterson, M. C., DeGraba, T., Parker, C. C., Zirzow, G. C., Oliver, K., Tedeschi, G., Brady, R. O., and Barton, N. W. 1997. Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease. Ann. Neurol. 42:613–621.
Grafe, M., Thomas, C., Schneider, J., Katz, B., and Wiley, C. 1988. Infantile Gaucher's disease: a case with neuronal storage. Ann. Neurol. 23:300–303.
Nilsson, O. and Svennerholm, L. 1982. Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J. Neurochem. 39:709–718.
Zirzow, G. C., Sanchez, O. A., Murray, G. J., Brady, R. O., and Oldfield, E. H. 1999. Delivery, distribution, and neuronal uptake of exogenous mannose-terminal glucocerebrosidase in the intact rat brain. Neurochem. Res. 24:301–305.
Stahl, P. D., Rodman, J. S., Miller, M. J., and Schlesinger, P. H. 1978. Evidence for receptor-mediated binding of glycoproteins, glycoconjugates, and lysosomal glycosidases by alveolar macrophages. Proc. Natl. Acad. Sci. USA 75:1399–1403.
Seeger, R. C., Rayner, S. A., Banerjee, A., Chung, H., Laug, W. E., Neustein, H. B., and Benedict, W. F. 1977. Morphology, growth, chromosomal pattern and fibrinolytic activity of two new human neuroblastoma cell lines. Cancer Res. 37:1364–1371.
Richardson, U. I., Liscovitch, M., and Blusztajn, J. K. 1989. Acetylcholine synthesis and secretion by LA-N-2 human neuroblastoma cells. Brain Res. 476:323–331.
Perez-Polo, J. R., Werbach-Perez, K., and Tiffany-Castiglioni, E. 1979. A human clonal cell line model of differentiating neurons. Dev. Biol. 71:341–355.
Spadari, S., Sala, F., and Pedrali-Noy, G. 1982. Aphidicolin: a specific inhibitor of nuclear DNA replication in eukaryotes. TIBS January:29–32.
Pedrali-Noy, G., Belvedere, M., Crepaldi, T., Focher, F., and Spadari, S. 1982. Inhibition of DNA replication and growth of several human and murine neoplastic cells by aphidicolin without detectable effect upon synthesis of immunoglobulins and HLA antigens. Cancer Res. 42:3810–3813.
Newburg, D. S., Yatziv, S., McCluer, R. H., and Raghavan, S. 1986. beta-Glucosidase inhibition in murine peritoneal macrophages by conduritol-B-epoxide: an in vitro model of the Gaucher cell. Biochim. Biophys. Acta 877:121–126.
Das, P. K., Murray, G. J., Gal, A. E., and Barranger, J. A. 1987. Glucocerebrosidase deficiency and lysosomal storage of glucocerebroside induced in cultured macrophages. Exp. Cell Res. 168:463–474.
Doebber, T. W., Wu, M. S., Bugianesi, R. L., Ponpipom, M. M., Furbish, F. S., Barranger, J. A., Brady, R. O., and Shen, T. Y. 1982. Enhanced macrophage uptake of synthetically glycosylated human placental beta-glucocerebrosidase. J. Biol. Chem. 257:2193–2199.
Suzuki, K. 1978. Enzymic diagnosis of sphingolipidoses. Methods Enzymol. 50:456–488.
Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J., and Klenk, D. C. 1985. Measurement of protein using bicinchoninic acid. Anal. Biochem. 150:76–85.
Barranger, J. A., Rapoport, S. I., Fredericks, W. R., Pentchev, P. G., MacDermot, K. D., Steusing, J. K., and Brady, R. O. 1979. Modification of the blood-brain barrier: increased concentration and fate enzymes entering the brain. Proc. Natl. Acad. Sci. USA 76:481–485.
Yamaguchi, Y., Dalle-Molle, E., and Hardison, W. G. 1993. Hepatocyte horseradish peroxidase uptake is saturable and inhibited by mannose-terminal glycoproteins. Am. J. Physiol. 264:G880–885.
Gray, J. S., Yang, B. Y., and Montgomery, R. 1998. Heterogeneity of glycans at each N-glycosylation site of horseradish peroxidase. Carbohydr. Res. 311:61–69.
Zanetta, J. P., Reeber, A., Dontenwill, M., and Vincendon, G. 1984. Evidence for the presence of lectins with mannose specificity in the rat cerebellum. J. Neurochem. 42:334–339.
Burudi, E. M. and Regnier-Vigouroux, A. 2001. Regional and cellular expression of the mannose receptor in the post-natal developing mouse brain. Cell Tissue Res. 303:307–317.
Schluff, P., Flott-Rahmel, B., Gieselmann, V., Zimmer, P., Das, A., and Ullrich, K. 1998. Localization of receptors for endocytosis of lysosomal enzymes on different brain cells. J. Inherit. Metab. Dis. 21:313–317.
Neudorfer, O., Giladi, N., Elstein, D., Abrahamov, A., Turezkite, T., Aghai, E., Reches, A., Bembi, B., and Zimran, A. 1996. Occurrence of Parkinson's syndrome in type I Gaucher disease. Qjm 89:691–694.
Machaczka, M., Rucinska, M., Skotnicki, A. B., and Jurczak, W. 1999. Parkinson's syndrome preceding clinical manifestation of Gaucher's disease. Am. J. Hematol. 61:216–217.
Tybulewicz, V. L., Tremblay, M. L., LaMarca, M. E., Willemsen, R., Stubblefield, B. K., Winfield, S., Zablocka, B., Sidransky, E., Martin, B. M., Huang, S. P., and et al. 1992. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 357:407–410.
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Schueler, U., Kaneski, C., Murray, G. et al. Uptake of Mannose-Terminal Glucocerebrosidase in Cultured Human Cholinergic and Dopaminergic Neuron Cell Lines. Neurochem Res 27, 325–330 (2002). https://doi.org/10.1023/A:1014915430398
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DOI: https://doi.org/10.1023/A:1014915430398