Niemann‐Pick C1 Pathophysiology Associates with Different Classes of Protein Trafficking Phenotypes Elicited by NPC‐1 Mutations
Authors: Shammas Hadeel , Rizk Sandra , Das Anibh , Naim Hassan Y. 
Published: June 2021

Niemann‐Pick Type C disease (NP‐C) is caused by a defect in the trafficking of endocytosed cholesterol with sequestration of cholesterol in lysosomes and late endosomes. Over 400 mutations have been identified in the NPC1 gene that account for almost 95 % of the NP‐C disease. It is still unclear how a mutation does affect the biosynthetic presentation and the intracellular localization of NPC1. We therefore asked whether mutations in the NPC1 gene generate different protein phenotypes that vary in their trafficking, intracellular localization and function, hence ultimately correlating with the pattern and severity of clinical symptoms in NP‐C patients. Three major classes of mutations could be identified based on the transport of NPC1 mutants along the secretory pathway, their association with lipid rafts and cellular localization. Many of the mutants analyzed were blocked in the ER as immature mannose‐rich proteins, while others were either partially trafficked through the Golgi to the lysosomes or trafficked in a comparable fashion to wild type NPC1. Interestingly, a particular trafficking phenotype is not elicited by mutations confined to a particular domain in NPC1, since these protein trafficking phenotypes arise from mutations that are distributed over different regions of NPC1. Furthermore, the interaction of the NPC1 mutants with lipid rafts varies among the different mutants analyzed in this study, indicating that their trafficking pattern could be associated with the reduced or abolished trafficking of cholesterol out of the lysosomes. Altogether, our study discloses a novel concept in the pathogenesis of NP‐C that relies on the diversity of the trafficking phenotypes of the NPC1 mutants. Expectedly, the ER‐located NPC1 mutants do not associate with lipid rafts since cholesterol or sphingolipids are not abundant in this organelle. On the other hand, the level of association of the partially‐trafficked mutants with lipid rafts is low and correlates with the level of maturation of these mutants. Remarkably, the correctly trafficked wild‐type‐like mutant NPC1‐L1213F as well as the wild type NPC1 varied substantially in their association levels with lipid rafts as compared to the other two classes. Nevertheless, the mature forms of the wild type‐like mutants revealed a higher solubility than their wild type counterpart, compatible with reduced levels of lipid rafts components in the cells overexpressing the mutant. Undoubtedly, membrane lipid analysis of cells overexpressing these mutants is required to support the hierarchical concept of trafficking. In conclusion, the current study proposes a direct link between the three classes of the NPC1 trafficking phenotype mutants, with the heterogeneous disease pattern including neurological, visceral, or psychiatric manifestations, hence the severity of NP‐C disease.Support or Funding InformationActelion, Switzerland to HYN; CNRS grant (CNRS‐01‐14‐12), Lebanon to SR; DAAD, Germany to HS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.