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

2017 ◽  
Vol 58 (4) ◽  
pp. 695-708 ◽  
Author(s):  
Nina H. Pipalia ◽  
Kanagaraj Subramanian ◽  
Shu Mao ◽  
Harold Ralph ◽  
Darren M. Hutt ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Niemann Pick ◽  
Cholesterol Storage ◽  
Mutant Cells

scholarly journals HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

2021 ◽  
Author(s):  
Nina H Pipalia ◽  
Syed Z Saad ◽  
Kangaraj Subramanian ◽  
Abigail Cross ◽  
Aisha Al-Motawa ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Cell Types ◽  
Hsp70 Expression ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Npc1 Gene ◽  
Abnormal Accumulation ◽  
Niemann Pick ◽  
Cholesterol Storage

Niemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study, we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in the clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see the correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. These results indicate that manipulation of molecular chaperones may lead to effective treatments for NPC1 disease, but further investigation of mechanisms will be required.

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

2016 ◽  
Author(s):  
Nina H. Pipalia ◽  
Kanagaraj Subramanian ◽  
Shu Mao ◽  
William E. Balch ◽  
Frederick R. Maxfield
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Autosomal Recessive Disorder ◽  
Fibroblast Cell ◽  
Common Mutation ◽  
Cholesterol Accumulation ◽  
Late Endosomes ◽  
Niemann Pick ◽  
Cholesterol Storage ◽  
Polytopic Membrane Protein

AbstractNiemann 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.

scholarly journals Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

2013 ◽  
Vol 10 (4) ◽  
pp. 688-697 ◽  
Author(s):  
Paul Helquist ◽  
Frederick R. Maxfield ◽  
Norbert L. Wiech ◽  
Olaf Wiest
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Type C ◽  
Niemann Pick

scholarly journals The potential of histone deacetylase inhibitors in Niemann - Pick type C disease

FEBS Journal ◽  
2013 ◽  
Vol 280 (24) ◽  
pp. 6367-6372 ◽  
Author(s):  
Michael Maceyka ◽  
Sheldon Milstien ◽  
Sarah Spiegel
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Type C ◽  
Niemann Pick
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