Targeting Molecular Chaperone HSP90 To Treat Niemann‐Pick Type C1 Disease

Abstract

NPC1 is a fatal, neurodegenerative lysosomal storage disease caused by mutations in the NPC1 gene. More than 300 different disease‐associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes/lysosomes (LE/Ly) of many cell types. There is no FDA‐approved therapy to treat NPC1 disease. A limited initial human trial of hydroxylpropyl beta cyclodextrin (HPBCD) is currently in progress. Our previous studies suggested that treatment with histone deacetylase inhibitors (HDACis) on skin fibroblasts results in increased expression of the NPC1 protein in mutant cells. Using an engineered human cell line, we have observed that HDACis can correct the NPC1 cholesterol storage defect in 60 of the 81 NPC1 mutants tested. However, when HDACis', were tested on non‐dividing cells like bone marrow derived macrophages, we did not observe any correction.Although, significant progress has been made in understanding the pathology of NPC1 disease, the mechanisms governing the proteostatic control of NPC1 protein is not well understood.. Disruption of molecular chaperone HSP90 (via hyperacetylation) is one of the many consequences of HDACi treatment. Thus, we evaluated the effect of direct inhibition of HSP90 family of proteins on NPC1 skin fibroblasts in terms of lowering lysosomal cholesterol accumulation.The data on the effect of several different HSP90 inhibitors on human patient‐derived skin fibroblast in lowering lysosomal cholesterol burden using microscopy based filipin assay will be presented. Our results suggests that cytosolic HSP90 and associated chaperones may be a target and that protein folding quality control plays a critical role in NPC1 diseases. We observed that out of the three HSP90 family proteins, inhibiting HSP90A and not HSP90B or TRAP resulted in clearance of cholesterol from lysosomes as well as aided in mobilizing unfolded mutant NPC1 protein from ER to lysosomes. We will also present the results elucidating the role of cytosolic HSP90 and its associated co‐chaperones in the regulation of NPC1 mutant protein stability.Support or Funding Information1. MDBR‐Orphan Disease UPenn Grant to Dr. Pipalia 2. APMRF Grant to Dr. Maxfield3. DART Summer Fellowship to Abigail CrossThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.