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Histone deacetylase inhibitors correct the cholesterol storage defect in most NPC1 mutant cells

View ORCID ProfileNina H. Pipalia, Kanagaraj Subramanian, Shu Mao, William E. Balch, View ORCID ProfileFrederick R. Maxfield
doi: https://doi.org/10.1101/076695
Nina H. Pipalia
aDepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA
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  • ORCID record for Nina H. Pipalia
Kanagaraj Subramanian
bDepartment of Chemical Physiology, and Cell and Molecular Biology. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, 92037, USA
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Shu Mao
aDepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA
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William E. Balch
bDepartment of Chemical Physiology, and Cell and Molecular Biology. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, 92037, USA
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  • For correspondence: webalch@scripps.edu
Frederick R. Maxfield
aDepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA
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  • ORCID record for Frederick R. Maxfield
  • For correspondence: frmaxfie@med.cornell.edu
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Abstract

Niemann Pick C disease (NPC) 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 (HDACi) Vorinostat or Panobinostat increases expression of the mutant NPC1 protein and leads to correction of the cholesterol storage. Herein 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 81 different NPC1 mutant constructs. The mutant NPC1 did not significantly reduce cholesterol accumulation, but approximately 80% of the mutants showed reduced cholesterol accumulation when treated with Vorinostat or Panobinostat.

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Posted September 23, 2016.
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Histone deacetylase inhibitors correct the cholesterol storage defect in most NPC1 mutant cells
Nina H. Pipalia, Kanagaraj Subramanian, Shu Mao, William E. Balch, Frederick R. Maxfield
bioRxiv 076695; doi: https://doi.org/10.1101/076695
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Histone deacetylase inhibitors correct the cholesterol storage defect in most NPC1 mutant cells
Nina H. Pipalia, Kanagaraj Subramanian, Shu Mao, William E. Balch, Frederick R. Maxfield
bioRxiv 076695; doi: https://doi.org/10.1101/076695

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