title: Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant alpha-galactosidase.
abstract: Peripheral neuropathy is one of the important manifestations of Fabry disease. Enzyme replacement therapy with presently available recombinant alpha-galactosidases does not always improve the Fabry neuropathy. But the reason has not been determined yet. We established a Schwann cell line from Fabry mice, characterized it, and then examined the uptake of alpha-galactosidase by cells and its effect on the degradation of accumulated substrate. The cells exhibited a distinct Schwann cell morphology and biochemical phenotype (alpha-Galactosidase activity was deficient, and numerous cytoplasmic inclusion bodies were present in the cells). A recombinant alpha-galactosidase added to the culture medium was incorporated into the cultured Fabry Schwann cells dose dependently. But the increase in cell-associated enzyme activity was less than that in the cases of human and mouse Fabry fibroblasts. The administration of a high dose of the enzyme improved the pathological changes in cells, although a low dose of it did not. Cellular uptake of the enzyme was strongly inhibited in the presence of mannose 6-phosphate. This suggests that the enzyme is incorporated via cation-independent mannose 6-phosphate receptors in Schwann cells. The low expression of cation-independent mannose 6-phosphate receptors in Schwann cells must be one of the reasons their uptake of the present enzymes was low. The administration of a high dose of the enzyme or the development of an enzyme containing many mannose 6-phosphate residues is required to improve Fabry neuropathy.
authors.affiliation: Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan.|Japan Science and Technology Agency, CREST, Kawaguchi, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawashima
authors.affiliation: Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Watabe
authors.affiliation: Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan.|Japan Science and Technology Agency, CREST, Kawaguchi, Japan.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Tajima
authors.affiliation: Department of Dermatology, Kagoshima University Graduate School of Medicine, Kagoshima, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fukushige
authors.affiliation: Department of Dermatology, Kagoshima University Graduate School of Medicine, Kagoshima, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kanzaki
authors.affiliation: Department of Dermatology, Kagoshima University Graduate School of Medicine, Kagoshima, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kanekura
authors.affiliation: Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Sugawara
authors.affiliation: Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
authors.forename: Naho
authors.initials: N
authors.lastname: Ohyanagi
authors.affiliation: Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
authors.forename: Tadayasu
authors.initials: T
authors.lastname: Togawa
authors.affiliation: Japan Science and Technology Agency, CREST, Kawaguchi, Japan. sakuraba@my-pharm.ac.jp.|Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan. sakuraba@my-pharm.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
mesh_terms: D000818:Animals; D001692:Biological Transport; D004305:Dose-Response Relationship, Drug; D000795:Fabry Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*
chemical_list: D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D000519:alpha-Galactosidase