Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells

• Published in: Journal of lipid research Vol. 58; no. 4; pp. 695 - 708
• Main Authors: Pipalia, Nina H., Subramanian, Kanagaraj, Mao, Shu, Ralph, Harold, Hutt, Darren M., Scott, Samantha M., Balch, William E., Maxfield, Frederick R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2017; Journal of Lipid Research; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Cell Line; Cell lines; cellular cholesterol; Cholesterol; Cholesterol - metabolism; cholesterol trafficking; drug therapy; Endoplasmic reticulum; Endoplasmic Reticulum-Associated Degradation - drug effects; Endosomes; Endosomes - metabolism; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Hereditary diseases; Heterozygotes; Histone deacetylase; Histone Deacetylase Inhibitors - administration & dosage; Humans; Hydroxamic Acids - administration & dosage; inborn errors of metabolism; Indoles - administration & dosage; Intracellular Signaling Peptides and Proteins; lipid transport; Lipids; Lysosomes; Lysosomes - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane proteins; Mutation; Niemann-Pick disease; Niemann-Pick Disease, Type C - drug therapy; Niemann-Pick Disease, Type C - genetics; Niemann-Pick Disease, Type C - metabolism; Niemann-Pick Disease, Type C - pathology; NPC1; Npc1 protein; Panobinostat; Proteins; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Transfection; Vorinostat; lipid transport; inborn errors of metabolism; drug therapy; NPC1; cellular cholesterol; cholesterol trafficking
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M072140

Niemann-Pick C (NPC) disease is an autosomal recessive disorder that leads to excessive storage of cholesterol and other lipids in late endosomes and lysosomes. The large majority of NPC disease is caused by mutations in NPC1, a large polytopic membrane protein that functions in late endosomes. There are many disease-associated mutations in NPC1, and most patients are compound heterozygotes. The most common mutation, NPC1I1061T, has been shown to cause endoplasmic reticulum-associated degradation of the NPC1 protein. Treatment of patient-derived NPC1I1061T fibroblasts with histone deacetylase inhibitors (HDACis) vorinostat or panobinostat increases expression of the mutant NPC1 protein and leads to correction of the cholesterol storage. Here, we show that several other human NPC1 mutant fibroblast cell lines can also be corrected by vorinostat or panobinostat and that treatment with vorinostat extends the lifetime of the NPC1I1061T protein. To test effects of HDACi on a large number of NPC1 mutants, we engineered a U2OS cell line to suppress NPC1 expression by shRNA and then transiently transfected these cells with 60 different NPC1 mutant constructs. The mutant NPC1 did not significantly reduce cholesterol accumulation, but approximately 85% of the mutants showed reduced cholesterol accumulation when treated with vorinostat or panobinostat.