Species-specific differences in NPC1 protein trafficking govern therapeutic response in Niemann-Pick type C disease

• DOI: 10.1172/jci.insight.160308
• Publication Date: 2022-10-27T16:00:56Z
• Authors: Mark L. Schultz; Kylie J. Schache; Ruth D. Azaria; Esmée Q. Kuiper; Steven Erwood; Evgueni A. Ivakine; Nicole Y. Farhat; Forbes D. Porter; Koralege C. Pathm...; Stephanie M. Cologna; Michael D. Uhler; Andrew P. Lieberman
• Keywords: NPC1; Niemann–Pick disease

The folding and trafficking of transmembrane glycoproteins are essential for cellular homeostasis compromised in many diseases. In Niemann-Pick type C disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, the glycoprotein NPC1 misfolds due to disease-causing missense mutations. While mutant has emerged as robust target proteostasis modulators, drug development efforts have been unsuccessful mouse models. Here, we demonstrated unexpected differences through medial Golgi between human I1061T-NPC1, common mutant. We established that these distinctions governed protein sequence rather than variations endoplasmic reticulum-folding environment. Moreover, direct effects on response small molecules modulate environment affecting Ca++ concentration. Finally, developed panel isogenic iNeurons expressing WT, I1061T-, R934L-NPC1 their utility testing candidate therapeutics. Our findings identify important rules governing NPC1's proteostatic modulators highlight importance species- mutation-specific responses therapy development.