Correction of Niemann-Pick type C1 trafficking and activity with the histone deacetylase inhibitor valproic acid

Kanagaraj Subramanian,Darren M Hutt,Samantha M Scott,Vijay Gupta,Shu Mao,William E Balch

doi:10.1074/jbc.ra119.010524

Abstract

Niemann-Pick type C (NPC) disease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments. The most prevalent disease-linked mutation is the I1061T variant of NPC1, which exhibits defective folding and trafficking from the endoplasmic reticulum to the LE/Ly compartments. We now show that the FDA-approved histone deacetylase inhibitor (HDACi) valproic acid (VPA) corrects the folding and trafficking defect associated with I1061T-NPC1 leading to restoration of cholesterol homeostasis, an effect that is largely driven by a reduction in HDAC7 expression. The VPA-mediated trafficking correction is in part associated with an increase in the acetylation of lysine residues in the cysteine-rich domain of NPC1. The HDACi-mediated correction is synergistically improved by combining it with the FDA-approved anti-malarial, chloroquine, a known lysosomotropic compound, which improved the stability of the LE/Ly-localized fraction of the I1061T variant. We posit that combining the activity of VPA, to modulate epigenetically the cellular acetylome, with chloroquine, to alter the lysosomal environment to favor stability of the trafficked I1061T variant protein can have a significant therapeutic benefit in patients carrying at least one copy of the I1061T variant of NPC1, the most common disease-associated mutation leading to NPC disease. Given its ability to cross the blood-brain barrier, we posit VPA provides a potential mechanism to improve the response to 2-hydroxypropyl-β-cyclodextrin, by restoring a functional NPC1 to the cholesterol managing compartment as an adjunct therapy.

Highlights

Niemann-Pick type C (NPC) disease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments
These results suggest that histone deacetylase inhibitor (HDACi) can restore CH homeostasis in patient-derived fibroblasts and heterologous models (59 –61), our screen did not include the blood-brain barrier (BBB) penetrant HDACi, valproic acid (VPA) (Fig. 1B)
We have previously shown that the HDACi-mediated correction of the trafficking defect associated with the F508del variant of cystic fibrosis transmembrane conductance regulator (CFTR) and the Z-variant (E342L) of ␣1-antitrypsin (AAT), which is the primary disease-linked variant leading to AAT deficiency, occurs through the suberoylanilide hydroxamic acid (SAHA)-mediated silencing of HDAC7 [71, 81]

Summary

Introduction

Niemann-Pick type C (NPC) disease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments. Despite the inability of either VPA or CQ to independently provide a significant increase in the stability of I1061T-NPC1, the combination of these 2 small molecules caused a significant improvement in the stability of this disease-associated variant, resulting in a WT-like 20% reduction in total I1061T NPC1 relative to the level seen at T ϭ 0 (Fig. 5E).

Results

Conclusion