Chemical chaperones for Niemann-Pick C disease

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DESCRIPTION (provided by applicant): NPC1 disease is a severe lysosomal lipidosis in which the egress of cholesterol and other lipids from the endosomal/ lysosomal (E/L) system is defective, leading to neurodegeneration and premature demise. The protein responsible for the major form of NPC disease, NPC1 is known. Preliminary characterization suggests that NPC1 may act as a lipid permease on the membranes of late endosomes. However, the exact function(s) of NPC1 and its role in NPC disease pathogenesis remain elusive and no form of treatment for this debilitating disorder is currently available. We hypothesize that many NPC1 mutations are disease causing due to the fact that the mutant proteins are unable to mature from the endoplasmic reticulum and are thus unable to be targeted to the late endosome. Pharmacologically relevant chemical chaperones have shown great promise recently in enhancing mutant protein maturation and thus partial rescue of protein activity. We will first establish an assay for detecting the maturation and ER exit of mutant NPC1 proteins. Second, we will use our in-house high throughput facility to identify chemical chaperones that can rescue mutant NPC1 proteins. These molecules will then be evaluated in cell-based assays to determine the level of NPC phenotype correction and assess their utility in future animal and NPC1 patient studies. Successful identification of small molecule chaperones will provide "Proof-of-principle" for this type of approach, and a new avenue of research for NPC1 and other devastating neurological disorders caused by membrane protein misfolding.