Glycosphingolipid storage in Fabry mice extends beyond globotriaosylceramide and is affected by ABCB1 depletion

Mustafa A Kamani; Philippe Provençal; Michel Boutin; Natalia Pacienza; Xin Fan; Anton Novak; Tonny C Huang; Beth Binnington; Bryan C Au; Christiane Auray-Blais; Clifford A Lingwood; Jeffrey A Medin

doi:10.4155/fsoa-2016-0027

Glycosphingolipid storage in Fabry mice extends beyond globotriaosylceramide and is affected by ABCB1 depletion

Future Sci OA. 2016 Oct 13;2(4):FSO147. doi: 10.4155/fsoa-2016-0027. eCollection 2016 Dec.

Affiliations

¹ University Health Network, Toronto, Ontario, M5G 1L7, Canada; University Health Network, Toronto, Ontario, M5G 1L7, Canada.
² Department of Pediatrics, Division of Medical Genetics, Université de Sherbrooke, CHUS, Hospital Fleurimont, Sherbrooke, Quebec, J1H 5N4, Canada; Department of Pediatrics, Division of Medical Genetics, Université de Sherbrooke, CHUS, Hospital Fleurimont, Sherbrooke, Quebec, J1H 5N4, Canada.
³ Division of Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Division of Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
⁴ Division of Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Departments of Biochemistry & Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; Division of Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Departments of Biochemistry & Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
⁵ University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.

Abstract

Aim: Fabry disease is caused by α-galactosidase A deficiency leading to accumulation of globotriaosylceramide (Gb₃) in tissues. Clinical manifestations do not appear to correlate with total Gb₃ levels. Studies examining tissue distribution of specific acyl chain species of Gb₃ and upstream glycosphingolipids are lacking.

Material & methods/results: Thorough characterization of the Fabry mouse sphingolipid profile by LC-MS revealed unique Gb₃ acyl chain storage profiles. Storage extended beyond Gb₃; all Fabry tissues also accumulated monohexosylceramides. Depletion of ABCB1 had a complex effect on glycosphingolipid storage.

Conclusion: These data provide insights into how specific sphingolipid species correlate with one another and how these correlations change in the α-galactosidase A-deficient state, potentially leading to the identification of more specific biomarkers of Fabry disease.

Keywords: ceramides; lipidomics; lysosomal storage disorders.