A therapy with miglustat, 2-hydroxypropyl-ß-cyclodextrin and allopregnanolone restores splenic cholesterol homeostasis in Niemann-pick disease type C1

• Main Authors: Anna-Maria Neßlauer, Anne Gläser, Markus Gräler, Robby Engelmann, Brigitte Müller-Hilke, Marcus Frank, Christine Burstein, Arndt Rolfs, John Neidhardt, Andreas Wree, Martin Witt, Anja U. Bräuer
• Format: Article
• Language: English
• Published: BMC 2019-06-01
• Series: Lipids in Health and Disease
• Subjects: Niemann-pick disease type C1; Spleen; Phospholipids; PRGs; G-protein-coupling receptor; qRT-PCR
• Online Access: http://link.springer.com/article/10.1186/s12944-019-1088-2

Abstract Background Niemann-Pick disease type C1 (NPC1) is an autosomal-recessive lipid-storage disorder with an estimated minimal incidence of 1/120,000 live births. Besides other neuronal and visceral symptoms, NPC1 patients develop spleen dysfunction, isolated spleno- or hepatosplenomegaly and infections. The mechanisms of splenomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Methods Here, we used an NPC1 mouse model to study a splenoprotective effect of a treatment with miglustat, 2-hydroxypropyl-ß-cyclodextrin and allopregnanolone and showed that this treatment has a positive effect on spleen morphology and lipid metabolism. Results Disease progress can be halted and blocked at the molecular level. Mutant Npc1 (Npc1 −/− ) mice showed increased spleen weight and increased lipid accumulation that could be avoided by our treatment. Also, FACS analyses showed that the increased number of splenic myeloid cells in Npc1 −/− mice was normalized by the treatment. Treated Npc1 −/− mice showed decreased numbers of cytotoxic T cells and increased numbers of T helper cells. Conclusions In summary, the treatment promotes normal spleen morphology, stabilization of lipid homeostasis and blocking of inflammation, but alters the composition of T cell subtypes.