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We have shown that the ABC transporter, multiple drug resistance protein 1 (MDR1, P-glycoprotein) translocates glucosyl ceramide from the cytosolic to the luminal Golgi surface for neutral, but not acidic, gly-cosphingolipid (GSL) synthesis. Here we show that the MDR1 inhibitor, cyclosporin A (CsA) can deplete Gaucher lymphoid cell lines of accumu-lated glucosyl ceramide and Fabry cell lines of globotriaosyl ceramide (Gb3), by preventing de novosynthesis. | iFEBS Journal Treatment of neutral glycosphingolipid lysosomal storage diseases via inhibition of the ABC drug transporter MDR1 Cyclosporin A can lower serum and liver globotriaosyl ceramide levels in the Fabry mouse model Michael Mattocks1 Maria Bagovich1 Maria De Rosa1 4 Steve Bond2 Beth Binnington1 Vanessa I. Rasaiah2 Jeffrey Medin2 3 and Clifford Lingwood1 4 5 1 Research Institute The Hospitalfor Sick Children Toronto Canada 2 Ontario Cancer Institute University Health Network Toronto Canada 3 Department of MedicalBiophysics University of Toronto Canada 4 Department of Laboratory Medicine and Pathology University of Toronto Canada 5 Department of Biochemistry University of Toronto Canada Keywords enzyme replacement therapy Gaucher disease a-galactosidase glucosyl ceramide translocase HUS model Correspondence C. Lingwood Research Institute The Hospital for Sick Children Toronto Ontario M5G 1X8 Canada Fax 416 813 5993 Tel 416 813 5998 E-mail cling@sickkids.ca Received 20 January 2006 revised 2 March 2006 accepted 10 March 2006 doi 10.1111 j.1742-4658.2006.05223.x We have shown that the ABC transporter multiple drug resistance protein 1 MDR1 P-glycoprotein translocates glucosyl ceramide from the cytosolic to the luminal Golgi surface for neutral but not acidic glycosphingolipid GSL synthesis. Here we show that the MDR1 inhibitor cyclosporin A CsA can deplete Gaucher lymphoid cell lines of accumulated glucosyl ceramide and Fabry cell lines of globotriaosyl ceramide Gb3 by preventing de novo synthesis. In the Fabry mouse model Gb3 is increased in the heart liver spleen brain and kidney. The lack of renal glomerular Gb3 is retained but the number of verotoxin 1 VT1 -staining renal tubules and VT1 tubular targeting in vivo is markedly increased in Fabry mice. Adult Fabry mice were treated with a-galactosidase enzymereplacement therapy ERT to eliminate serum Gb3 and lower Gb3 levels in some tissues. Serum Gb3 was monitored using a VT1 ELISA during a post-ERT recovery .
