The paper by Yu et al. reports a strategy for modulating  cellular proteostasis and restore functional activity of NPC1 in primary fibroblasts of patients with Niemann–Pick type C disease. The authors of this paper found that ryanodine receptor (RyR) antagonists increased steady-state NPC1 levels in fibroblasts carrying the p.I1061T mutation, which is degraded by the proteasome. These compounds also promoted trafficking of mutant NPC1 to late endosomes and lysosomes and rescued the aberrant storage of cholesterol and sphingolipids that is characteristic of disease. This study highlights the efficacy and the therapeutic potential of proteostasis regulators to recover function of NPC1 mutated proteins.

Yu T, Chung C, Shen D, Xu H, Lieberman AP.Ryanodine receptor antagonists adapt NPC1 proteostasis to ameliorate lipid storage in Niemann-Pick type C disease fibroblasts. Hum Mol Genet. 2012 Apr 25. [Epub ahead of print]

OMMBID Part 16: LYSOSOMAL DISORDERS, chapter 145: Niemann-Pick Disease Type C: A Lipid Trafficking Disorder

Nicola Brunetti-Pierri, MD, FACMG