Journal
JOURNAL OF LIPID RESEARCH
Volume 58, Issue 4, Pages 695-708Publisher
ELSEVIER
DOI: 10.1194/jlr.M072140
Keywords
NPC1; cellular cholesterol; lipid transport; inborn errors of metabolism; drug therapy; cholesterol trafficking
Categories
Funding
- National Institute of Neurological Disorders and Stroke [R01-NS092653]
- National Institute of Diabetes and Digestive and Kidney Diseases [R37DK27083]
- Ara Parseghian Medical Research Foundation
Ask authors/readers for more resources
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, NPC1(I1061T), has been shown to cause endoplasmic reticulum-associated degradation of the NPC1 protein. Treatment of patient-derived NPC1(I1061T) 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 NPC1(I1061T) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available