Advertisement

Virchows Archiv

, Volume 451, Issue 4, pp 823–834 | Cite as

Cellular and tissue localization of globotriaosylceramide in Fabry disease

  • Hasan Askari
  • Christine R. Kaneski
  • Cristina Semino-Mora
  • Priya Desai
  • Agnes Ang
  • David E. Kleiner
  • Lorah T. Perlee
  • Martha Quezado
  • Linda E. Spollen
  • Brandon A. Wustman
  • Raphael SchiffmannEmail author
Original Article

Abstract

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.

Keywords

Glycolipids Immunohistochemistry Electron microscopy Lysosomal disorder Lysosome 

Notes

Acknowledgments

We thank the NINDS EM facility for expert technical help in the pre-embedding immunogold technique. This study was funded by the Intramural Program of the National Institute of Neurological Disorders and Stroke and the National Cancer Institute. The authors do not have financial conflict of interest that is relevant to this study. Dr. Brandon A. Wustman is employed by Amicus Therapeutics that develops pharmacological chaperones for the treatment of lysosomal diseases.

References

  1. 1.
    Altarescu G, Moore DF, Pursley R, Campia U, Goldstein S, Bryant M, Panza JA, Schiffmann R (2001) Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke 32:1559–1562PubMedGoogle Scholar
  2. 2.
    Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ (2007) Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 146:77–86PubMedGoogle Scholar
  3. 3.
    Bendayan M, Nanci A, Kan FW (1987) Effect of tissue processing on colloidal gold cytochemistry. J Histochem Cytochem 35:983–996PubMedGoogle Scholar
  4. 4.
    Bodary PF, Shen Y, Vargas FB, Bi X, Ostenso KA, Gu S, Shayman JA, Eitzman DT (2005) Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency. Circulation 111:629–632PubMedCrossRefGoogle Scholar
  5. 5.
    Brady R, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L (1967) Enzymatic defect in Fabry disease: ceramide trihexosidase deficiency. N Engl J Med 276:1163–1167PubMedCrossRefGoogle Scholar
  6. 6.
    Brady RO, Schiffmann R (2000) Clinical features of and recent advances in therapy for Fabry disease. JAMA 284:2771–2775PubMedCrossRefGoogle Scholar
  7. 7.
    d’Azzo A, Tessitore A, Sano R (2006) Gangliosides as apoptotic signals in ER stress response. Cell Death Differ 13:404–414PubMedCrossRefGoogle Scholar
  8. 8.
    Desnick RJ, Ioannou YA, Eng CM (2001) a-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 3733–3774Google Scholar
  9. 9.
    Fukushima M, Tsuchiyama Y, Nakato T, Yokoi T, Ikeda H, Yoshida S, Kusumoto T, Itoh K, Sakuraba H (1995) A female heterozygous patient with Fabry’s disease with renal accumulation of trihexosylceramide detected with a monoclonal antibody. Am J Kidney Dis 26:952–955PubMedGoogle Scholar
  10. 10.
    Futerman AH (2006) Intracellular trafficking of sphingolipids: relationship to biosynthesis. Biochim Biophys Acta 1758:1885–1892PubMedCrossRefGoogle Scholar
  11. 11.
    Garner B, Priestman DA, Stocker R, Harvey DJ, Butters TD, Platt FM (2002) Increased glycosphingolipid levels in serum and aortae of apolipoprotein E gene knockout mice. J Lipid Res 43:205–214PubMedGoogle Scholar
  12. 12.
    Hogerkorp CM, Borrebaeck CA (2006) The human CD77- B cell population represents a heterogeneous subset of cells comprising centroblasts, centrocytes, and plasmablasts, prompting phenotypical revision. J Immunol 177:4341–4349PubMedGoogle Scholar
  13. 13.
    Itoh K, Takenaka T, Nakao S, Setoguchi M, Tanaka H, Suzuki T, Sakuraba H (1996) Immunofluorescence analysis of trihexosylceramide accumulated in the hearts of variant hemizygotes and heterozygotes with Fabry disease. Am J Cardiol 78:116–117PubMedCrossRefGoogle Scholar
  14. 14.
    Kacher Y, Futerman AH (2006) Genetic diseases of sphingolipid metabolism: pathological mechanisms and therapeutic options. FEBS Lett 580:5510–5517PubMedCrossRefGoogle Scholar
  15. 15.
    Kanda A, Nakao S, Tsuyama S, Murata F, Kanzaki T (2000) Fabry disease: ultrastructural lectin histochemical analyses of lysosomal deposits. Virchows Arch 436:36–42PubMedCrossRefGoogle Scholar
  16. 16.
    Kanekura T, Fukushige T, Kanda A, Tsuyama S, Murata F, Sakuraba H, Kanzaki T (2005) Immunoelectron-microscopic detection of globotriaosylceramide accumulated in the skin of patients with Fabry disease. Br J Dermatol 153:544–548PubMedCrossRefGoogle Scholar
  17. 17.
    Kaye EM, Kolodny EH, Logigian EL, Ullman MD (1988) Nervous system involvement in Fabry's disease: clinicopathological and biochemical correlation. Ann Neurol 23:505–509PubMedCrossRefGoogle Scholar
  18. 18.
    Khine AA, Firtel M, Lingwood CA (1998) CD77-dependent retrograde transport of CD19 to the nuclear membrane: functional relationship between CD77 and CD19 during germinal center B-cell apoptosis. J Cell Physiol 176:281–292PubMedCrossRefGoogle Scholar
  19. 19.
    Kotani M, Kawashima I, Ozawa H, Ogura K, Ariga T, Tai T (1994) Generation of one set of murine monoclonal antibodies specific for globo-series glycolipids: evidence for differential distribution of the glycolipids in rat small intestine. Arch Biochem Biophys 310:89–96PubMedCrossRefGoogle Scholar
  20. 20.
    Lee MC, Miller EA, Goldberg J, Orci L, Schekman R (2004) Bi-directional protein transport between the ER and Golgi. Annu Rev Cell Dev Biol 20:87–123PubMedCrossRefGoogle Scholar
  21. 21.
    Lingwood CA (1999) Verotoxin/globotriaosyl ceramide recognition: angiopathy, angiogenesis and antineoplasia. Biosci Rep 19:345–354PubMedCrossRefGoogle Scholar
  22. 22.
    Lloyd-Evans E, Pelled D, Riebeling C, Bodennec J, de-Morgan A, Waller H, Schiffmann R, Futerman AH (2003) Glucosylceramide and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms. J Biol Chem 278:23594–23599PubMedCrossRefGoogle Scholar
  23. 23.
    Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N et al (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529PubMedCrossRefGoogle Scholar
  24. 24.
    Miyamoto D, Ueno T, Takashima S, Ohta K, Miyawaki T, Suzuki T, Suzuki Y (1997) Establishment of a monoclonal antibody directed against Gb3Cer/CD77: a useful immunochemical reagent for a differentiation marker in Burkitt’s lymphoma and germinal centre B cells. Glycoconj J 14:379–388PubMedCrossRefGoogle Scholar
  25. 25.
    Miyatake T (1969) A study on glycolipids in Fabry’s disease. Jpn J Exp Med 38:135–138Google Scholar
  26. 26.
    Mogami K, Kishi H, Kobayashi S (2005) Sphingomyelinase causes endothelium-dependent vasorelaxation through endothelial nitric oxide production without cytosolic Ca(2+) elevation. FEBS Lett 579:393–397PubMedCrossRefGoogle Scholar
  27. 27.
    Moore D, Scott LJC, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, Pease-Fye M, Ferri R, Brady RO, Herscovitch P, Schiffmann R (2001) Regional cerebral hyper-perfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation 104:1506–1512PubMedGoogle Scholar
  28. 28.
    Moore DF, Krokhin OV, Beavis RC, Ries M, Robinson C, Goldin E, Brady RO, Wilkins JA, Schiffmann R (2007) Proteomics of specific treatment-related alterations in Fabry disease: a strategy to identify biological abnormalities. Proc Natl Acad Sci USA 104:2873–2878PubMedCrossRefGoogle Scholar
  29. 29.
    Ogawa K, Sugamata K, Funamoto N, Abe T, Sato T, Nagashima K, Ohkawa S (1990) Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry’s disease. Human Pathol 21:1067–1073CrossRefGoogle Scholar
  30. 30.
    Olivero OA, Semino C, Poirier MC (1990) Localization of DNA adducts induced by N-acetoxy-N-2-acetylaminofluorene in Chinese hamster ovary cells using electron microscopy and colloidal gold. Genes Chromosomes Cancer 2:130–136PubMedCrossRefGoogle Scholar
  31. 31.
    Oosterwijk E, Kalisiak A, Wakka JC, Scheinberg DA, Old LJ (1991) Monoclonal antibodies against Gal alpha 1-4Gal beta 1-4Glc (Pk, CD77) produced with a synthetic glycoconjugate as immunogen: reactivity with carbohydrates, with fresh frozen human tissues and hematopoietic tumors. Int J Cancer 48:848–854PubMedCrossRefGoogle Scholar
  32. 32.
    Pagano RE (2003) Endocytic trafficking of glycosphingolipids in sphingolipid storage diseases. Philos Trans R Soc Lond B Biol Sci 358:885–891PubMedCrossRefGoogle Scholar
  33. 33.
    Paton JC, Paton AW (1998) Pathogenesis and diagnosis of Shiga toxin-producing Escherichia coli infections. Clin Microbiol Rev 11:450–479PubMedGoogle Scholar
  34. 34.
    Pelled D, Lloyd-Evans E, Riebeling C, Jeyakumar M, Platt FM, Futerman AH (2003) Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase in a mouse model of Sandhoff disease and prevention by treatment with N-butyldeoxynojirimycin. J Biol Chem 278:29496–29501PubMedCrossRefGoogle Scholar
  35. 35.
    Pelled D, Trajkovic-Bodennec S, Lloyd-Evans E, Sidransky E, Schiffmann R, Futerman AH (2005) Enhanced calcium release in the acute neuronopathic form of Gaucher disease. Neurobiol Dis 18:83–88PubMedCrossRefGoogle Scholar
  36. 36.
    Rozenfeld PA, Croxatto O, Ebner R, Fossati CA (2006) Immunofluorescence detection of globotriaosylceramide deposits in conjunctival biopsies of Fabry disease patients. Clin Exp Ophthalmol 34:689–694CrossRefGoogle Scholar
  37. 37.
    Schibanoff JM, Kamoshita S, O’Brien JS (1969) Tissue distribution of glycosphingolipids in a case of Fabry’s disease. J Lipid Res 10:515–520PubMedGoogle Scholar
  38. 38.
    Schiffmann R, Floeter MK, Dambrosia JM, Gupta S, Moore DF, Sharabi Y, Khurana RK, Brady RO (2003) Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 28:703–710PubMedCrossRefGoogle Scholar
  39. 39.
    Schiffmann R, Rapkiewicz A, Abu-Asab M, Ries M, Askari H, Tsokos M, Quezado M (2006) Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement. Virchows Arch 448:337–343PubMedCrossRefGoogle Scholar
  40. 40.
    Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO (2006) Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrol Dial Transplant 21:345–354PubMedCrossRefGoogle Scholar
  41. 41.
    Semino-Mora C, Dalakas MC (1998) Rimmed vacuoles with beta-amyloid and ubiquitinated filamentous deposits in the muscles of patients with long-standing denervation (postpoliomyelitis muscular atrophy): similarities with inclusion body myositis. Human Pathol 29:1128–1133CrossRefGoogle Scholar
  42. 42.
    Stirling JW, Graff PS (1995) Antigen unmasking for immunoelectron microscopy: labeling is improved by treating with sodium ethoxide or sodium metaperiodate, then heating on retrieval medium. J Histochem Cytochem 43:115–123PubMedGoogle Scholar
  43. 43.
    Tao-Cheng JH, Vinade L, Smith C, Winters CA, Ward R, Brightman MW, Reese TS, Dosemeci A (2001) Sustained elevation of calcium induces Ca(2+)/calmodulin-dependent protein kinase II clusters in hippocampal neurons. Neuroscience 106:69–78PubMedCrossRefGoogle Scholar
  44. 44.
    Tessitore A, del PMM, Sano R, Ma Y, Mann L, Ingrassia A, Laywell ED, Steindler DA, Hendershot LM, d’Azzo A (2004) GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell 15:753–766PubMedCrossRefGoogle Scholar
  45. 45.
    Tetaud C, Falguieres T, Carlier K, Lecluse Y, Garibal J, Coulaud D, Busson P, Steffensen R, Clausen H, Johannes L, Wiels J (2003) Two distinct Gb3/CD77 signaling pathways leading to apoptosis are triggered by anti-Gb3/CD77 mAb and verotoxin-1. J Biol Chem 278:45200–45208PubMedCrossRefGoogle Scholar
  46. 46.
    Walkley SU (1995) Pyramidal neurons with ectopic dendrites in storage diseases exhibit increased GM2 ganglioside immunoreactivity. Neuroscience 68:1027–1035PubMedCrossRefGoogle Scholar
  47. 47.
    Walkley SU, Thrall MA, Haskins ME, Mitchell TW, Wenger DA, Brown DE, Dial S, Seim H (2005) Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux–Lamy) disease. Neuropathol Appl Neurobiol 31:536–544PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Hasan Askari
    • 1
  • Christine R. Kaneski
    • 1
  • Cristina Semino-Mora
    • 2
  • Priya Desai
    • 3
  • Agnes Ang
    • 3
  • David E. Kleiner
    • 4
  • Lorah T. Perlee
    • 3
  • Martha Quezado
    • 4
  • Linda E. Spollen
    • 5
  • Brandon A. Wustman
    • 6
  • Raphael Schiffmann
    • 1
    Email author
  1. 1.Developmental and Metabolic Neurology Branch, NINDSNational Institutes of HealthBethesdaUSA
  2. 2.Laboratory of Gastrointestinal and Liver StudiesUniformed Services University of the Health SciencesBethesdaUSA
  3. 3.HistoRxNew HavenUSA
  4. 4.Laboratory of Pathology, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  5. 5.Department of PathologyUniversity of Missouri Hospitals and ClinicsColumbiaUSA
  6. 6.Amicus TherapeuticsCranburyUSA

Personalised recommendations