Mutant induced neurons and humanized mice enable identification of Niemann-Pick type C1 proteostatic therapies.

ABSTRACT: Therapeutics that rescue folding, trafficking, and function of disease-causing missense mutants are sought for a host of human diseases, but efforts to leverage model systems to test emerging strategies have met with limited success. Such is the case for Niemann-Pick type C1 disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, progressive neurodegeneration, and early death. NPC1, a multipass transmembrane glycoprotein, is synthesized in the endoplasmic reticulum and traffics to late endosomes/lysosomes, but this process is often disrupted in disease. We sought to identify small molecules that promote folding and enable lysosomal localization and functional recovery of mutant NPC1. We leveraged a panel of isogenic human induced neurons expressing di

SUBMITTER: Azaria RD 

PROVIDER: S-EPMC11530122 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature