Cellular and tissue localization of globotriaosylceramide in Fabry disease.
The pathogenesis of Fabry disease is poorly understood. We used a variety of immunohistological techniques to localize globotriaosylceramide, the main glycolipid that accumulates in Fabry disease. Globotriaosylceramide immunoreactivity in a heterogenous pattern was present in all organs examined of a patient on long-term enzyme replacement therapy. In the brain, immmunopositivity was found only in the parahippocampal region. Globotriaosylceramide immunostaining was present in the cell membrane and cytoplasm of endothelial cells, even in the absence of lysosomal inclusions. In kidney tissue, globotriaosylceramide colocalized with lysosomal, endoplasmic reticulum, and nuclear markers. Pre- and postembedding immunogold electron microscopy of skin biopsies and untreated patient cultured skin fibroblasts confirmed the presence of globotriaosylceramide in the cell membrane, in various cytoplasmic structures, and in the nucleus. Control organ tissues and cultured fibroblasts from five unaffected subjects were uniformly negative for globotriaosylceramide by immunohistochemistry and immunogold electron microscopy. We conclude that a substantial amount of lysosomal and extralysosomal globotriaosylceramide immunoreactivity remains in cells and tissues even after years of enzyme replacement therapy in Fabry disease. These findings are crucial for the understanding of the disease mechanism and suggest the usefulness of immunostaining for globotriaosylceramide as a means to assess response to novel, specific therapies.
Askari
Hasan
H
Developmental and Metabolic Neurology Branch, NINDS, National Institutes of Health, Building 10, Room 3D03, 9000 Rockville Pike, Bethesda, MD 20892-1260, USA.
Kaneski
Christine R
CR
Semino-Mora
Cristina
C
Desai
Priya
P
Ang
Agnes
A
Kleiner
David E
DE
Perlee
Lorah T
LT
Quezado
Martha
M
Spollen
Linda E
LE
Wustman
Brandon A
BA
Schiffmann
Raphael
R
D000328:Adult; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D000795:Fabry Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008875:Middle Aged; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014281:Trihexosylceramides / Q000378:metabolism*
D014281:Trihexosylceramides; C018549:globotriaosylceramide