Ryanodine receptor antagonists adapt NPC1 proteostasis to ameliorate lipid storage in Niemann-Pick type C disease fibroblasts.

ABSTRACT: Niemann-Pick type C disease is a lysosomal storage disorder most often caused by loss-of-function mutations in the NPC1 gene. The encoded multipass transmembrane protein is required for cholesterol efflux from late endosomes and lysosomes. Numerous missense mutations in the NPC1 gene cause disease, including the prevalent I1061T mutation that leads to protein misfolding and degradation. Here, we sought to modulate the cellular proteostasis machinery to achieve functional recovery in primary patient fibroblasts. We demonstrate that targeting endoplasmic reticulum (ER) calcium levels using ryanodine receptor (RyR) antagonists increased steady-state levels of the NPC1 I1061T protein. These compounds also promoted trafficking of mutant NPC1 to late endosomes and lysosomes and rescued the aberr

SUBMITTER: Yu T 

PROVIDER: S-EPMC3384383 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature