Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium

  title={Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium},
  author={Emyr Lloyd-Evans and Anthony J. Morgan and Xingxuan He and David A Smith and Elena Elliot-Smith and Daniel Sillence and Grant C. Churchill and Edward H. Schuchman and Antony Galione and Frances M. Platt},
  journal={Nature Medicine},
Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic… 

Interplay between sphingolipid and nutriente signaling in niemann-pick type C1 disease: new clues from a yeast cell model

The results show that ncr1Δ mutant cells display a high sensitivity to oxidative stress induced by hydrogen peroxide that is associated with increased levels of oxidative stress markers, such as protein oxidation, lipid peroxidation and intracellular reactive oxygen species (ROS) levels, impairment of antioxidant defenses and mitochondrial dysfunctions, Taken together, these changes contribute to a shortened chronological lifespan in ncr2Δ cells.

Niemann-Pick type C disease: The atypical sphingolipidosis.

Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation

The results indicate that a SphK 1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells, highlighting a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

Complex lipid trafficking in Niemann-Pick disease type C

  • M. Vanier
  • Biology, Chemistry
    Journal of Inherited Metabolic Disease
  • 2014
A reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models is provided, with emphasis on differences between systemic organs and the brain.

Crohn’s Disease in Niemann–Pick Disease Type C1: Caught in the Cross-Fire of Host-Microbial Interactions

Results suggest that lipophagy is key for understanding many aspects of the NPC1 phenotype, and identify mild histological hallmarks of intestinal inflammation including crypt abscesses.

Defective platelet function in Niemann‐Pick disease type C1

Electron microscopy revealed abnormal ultrastructure in murine platelets, consistent with that seen in a U18666A treated megakaryocyte cell line (MEG‐01) exhibiting lipid storage and acidic compartment Ca2+ flux defects.

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

A better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.

The role of eisosomes and calcineurin in a yeast model of Niemann-Pick type C 1 Rúben

How eisosomes, regulators of Pkh1-Ypk 1 signalling, and Ypk1 impact the regulation of sphingolipid synthesis and in the cellular death phenotypes of Niemann-Pick type C1 is characterized.

Cholesterol in Niemann-Pick Type C disease.

This chapter reviews recent achievements in the investigation of disruption of cholesterol homeostasis-induced neurodegeneration in NPC disease, and provides new insight for developing a potential therapeutic strategy for this disorder.



Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.

It is demonstrated that NPC-variant fibroblast samples can be detected as sphingolipid storage disease cells, using a fluorescent sphingoipid analog, BODIPY-lactosylceramide, and found that 5 of the 12 variant cell samples had no apparent defect in NPC1 but were otherwise indistinguishable from other variant cells.

Accumulation of Glycosphingolipids in Niemann-Pick C Disease Disrupts Endosomal Transport*

It is suggested that accumulating GSL is part of a mislocalized membrane microdomain and is responsible for the deficit in endocytic trafficking found in Niemann-Pick type C disease.

Treatment with miglustat reverses the lipid-trafficking defect in Niemann–Pick disease type C

Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C–related protein reveals a primordial role in subcellular sphingolipid distribution

It is proposed that the primordial function of these proteins is to recycle sphingolipids and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation.

Therapy of Niemann-Pick disease, type C.

Purified NPC1 Protein

The sterol binding site on luminal loop-1 is not essential for NPC1 function in fibroblasts, but it may function in other cells where NPC1 deficiency produces more complicated lipid abnormalities.

Development of an assay for the intermembrane transfer of cholesterol by Niemann-Pick C2 protein

A cell-free assay for measuring intermembrane lipid transport and identifying for the first time the ability of other lysosomal proteins, most notably the GM2-activator protein, to mediate inter Membrane cholesterol transfer are identified.

Transmembrane molecular pump activity of Niemann-Pick C1 protein.

Evidence is provided that the NPC1 protein has homology with the resistance-nodulation-division family of prokaryotic permeases and may normally function as a transmembrane efflux pump and establish NPC1 as a eukaryotic member of the RND permease family.

Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease.

A functional role of S1P synthesis and receptor expression in astrocyte proliferation leading to astrogliosis during the terminal stages of neurodegeneration in Sandhoff disease mice is demonstrated.