Targeting molecular chaperone HSP90 to treat Niemann‐Pick type C1 disease

Abstract

NPC1 is a fatal, lysosomal neurovisceral storage disease caused by mutations in the npc1 gene. More than 200 different disease‐associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosome/ lysosomes (LE/Ly) of many cell types. There is no FDA‐approved therapy to treat NPC1 disease. A limited initial human trial of hydroxyl propyl cyclodextrin (HPCD) is currently in progress, but HPCD does not cross the BBB. Based on our previous findings on NPC1I1061T skin fibroblast, a small clinical trial is also in progress on the treatment of histone deacetylase inhibitor (HDACi), Vorinostat. Our data suggested that HDACi treatment on skin fibroblasts results in increased expression of the Niemann‐Pick type C1 (NPC1) protein in mutant cells. Using an engineered human cell line, we have also observed that HDACis, can correct the NPC1 cholesterol storage defect in 60 of the 81 NPC1 mutants tested. Although significant progress has been made in understanding the pathology of NPC1 disease, the mechanisms governing the proteostatic control of NPC1 protein is not completely understood. However, being an epigenetic modifier, HDACi is known to alter the pattern of gene expression. As a result, off‐target effects are of a major concern in using HDACi's as a therapy. In order to understand the molecular mechanism of HDACi on NPC1, we considered potential cellular targets of HDACi other than histones. Disruption of molecular chaperone HSP90 (via hyperacetylation) is one of the many consequences of HDACi treatment.We, therefore, evaluated the effect of direct inhibition of HSP90 family of proteins on NPC1 skin fibroblasts in terms of lowering lysosomal cholesterol accumulation. Our results indicated that out of the three HSP90 family proteins, selectively HSP90A and not HSP90B or TRAP inhibition resulted in clearance of cholesterol from lysosomes as well as aided in mobilizing unfolded mutant NPC1 protein from ER to lysosomes. Hence the data on the effect of several different HSP90 inhibitors on multiple human patient‐derived skin fibroblast in lowering lysosomal cholesterol burden using microscopy based filipin assay will be presented. Our previous published work using HDACi and recent preliminary results using heat shock protein HSP90 inhibitors suggests that cytosolic HSP90 and associated chaperones may be a target and indicates that protein folding quality control plays a critical role in NPC1 diseases. An attempt will be made to elucidate the role of cytosolic HSP90 and its associated co‐chaperones in the regulation of NPC1 mutant protein stability.Support or Funding InformationAra Parseghian Medical Research FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.