title: FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts.
abstract: Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations inNPC1orNPC2with decreased functions leading to lysosomal accumulation of cholesterol and sphingolipids. FTY720/fingolimod, used for treatment of multiple sclerosis, is phosphorylated by nuclear sphingosine kinase 2, and its active phosphorylated form (FTY720-P) is an inhibitor of class I histone deacetylases. In this study, administration of clinically relevant doses of FTY720 to mice increased expression of NPC1 and -2 in brain and liver and decreased cholesterol in an SphK2-dependent manner. FTY720 greatly increased expression of NPC1 and -2 in humanNPC1mutant fibroblasts that correlated with formation of FTY720-P and significantly reduced the accumulation of cholesterol and glycosphingolipids. In agreement with this finding, FTY720 pretreatment of humanNPC1mutant fibroblasts restored transport of the cholera toxin B subunit, which binds ganglioside GM1, to the Golgi apparatus. Together, these findings suggest that FTY720 administration can ameliorate cholesterol and sphingolipid storage and trafficking defects inNPC1mutant fibroblasts. Because neurodegeneration is the main clinical feature of NPC disease, and FTY720 accumulates in the CNS and has several advantages over available histone deacetylase inhibitors now in clinical trials, our work provides a potential opportunity for treatment of this incurable disease.-Newton, J., Hait, N. C., Maceyka, M., Colaco, A., Maczis, M., Wassif, C. A., Cougnoux, A., Porter, F. D., Milstien, S., Platt, N., Platt, F. M., Spiegel, S. FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Newton
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Maceyka
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom; and.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Colaco
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Maczis
authors.affiliation: Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.affiliation: Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Cougnoux
authors.affiliation: Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom; and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Platt
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom; and.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; sarah.spiegel@vcuhealth.org.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C497045:Npc2 protein, mouse; D011506:Proteins; D013107:Sphingolipids; D033921:Vesicular Transport Proteins; D002784:Cholesterol; D000068876:Fingolimod Hydrochloride
keywords: glycosphingolipids; histone deacetylase inhibitor; lipid storage disease; sphingosine kinase