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


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.

SUBMITTER: Neßlauer AM 

PROVIDER: S-EPMC6598286 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Neßlauer Anna-Maria AM   Gläser Anne A   Gräler Markus M   Engelmann Robby R   Müller-Hilke Brigitte B   Frank Marcus M   Burstein Christine C   Rolfs Arndt A   Neidhardt John J   Wree Andreas A   Witt Martin M   Bräuer Anja U AU  

Lipids in health and disease 20190628 1


<h4>Background</h4>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.<h4>Methods</h4>Here, we used an NPC1 mouse model to study a splen  ...[more]

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