Journal ArticleDOI
Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium
Emyr Lloyd-Evans,Anthony J. Morgan,Xingxuan He,David Smith,Elena Elliot-Smith,Daniel J. Sillence,Grant C. Churchill,Edward H. Schuchman,Antony Galione,Frances M. Platt +9 more
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TLDR
It is found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells, which represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.Abstract:
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 calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.read more
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Signals from the lysosome: a control centre for cellular clearance and energy metabolism.
TL;DR: The identification of a master regulator, transcription factor EB (TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the lyssome adapts to environmental cues, such as starvation, and targeting TFEB may provide a novel therapeutic strategy for modulating lysOSomal function in human disease.
Journal ArticleDOI
Ebola virus entry requires the cholesterol transporter Niemann–Pick C1
Jan E. Carette,Jan E. Carette,Matthijs Raaben,Anthony C. Wong,Andrew S. Herbert,Gregor Obernosterer,Gregor Obernosterer,Nirupama Mulherkar,Ana I. Kuehne,Philip J. Kranzusch,April M. Griffin,Gordon Ruthel,Paola Dal Cin,John M. Dye,Sean P. J. Whelan,Kartik Chandran,Thijn R. Brummelkamp,Thijn R. Brummelkamp +17 more
TL;DR: It is shown that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport, which indicates potential antiviral strategies to combat these deadly agents.
Journal ArticleDOI
Niemann-Pick disease type C
TL;DR: The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin, and genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis.
Journal ArticleDOI
Glycosylation in health and disease.
TL;DR: The broad role of glycans in immunity, cancer, xenotransplantation and glomerular filtration and the potential of ‘glycomedicine’ are discussed.
Journal ArticleDOI
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities
Fiona M. Menzies,Angeleen Fleming,Andrea Caricasole,Carla F. Bento,Stephen P. Andrews,Avraham Ashkenazi,Jens Füllgrabe,Anne Jackson,Maria Jimenez Sanchez,Cansu Karabiyik,Floriana Licitra,Ana Lopez Ramirez,Mariana Pavel,Claudia Puri,Maurizio Renna,Thomas Ricketts,Lars Schlotawa,Mariella Vicinanza,Hyeran Won,Ye Zhu,John Skidmore,David C. Rubinsztein +21 more
TL;DR: How autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions is described and possible pathways and druggable targets that may be suitable for this objective are considered.
References
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Journal ArticleDOI
Identification of HE1 as the Second Gene of Niemann-Pick C Disease
Saule Naureckiene,David E. Sleat,David E. Sleat,Henry Lackland,Anthony H. Fensom,Marie T. Vanier,Robert Wattiaux,Michel Jadot,Peter Lobel,Peter Lobel +9 more
TL;DR: Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.
Journal ArticleDOI
Niemann-Pick disease type C.
Marie T. Vanier,Gilles Millat +1 more
TL;DR: Identification of mutations revealed a complex picture of molecular heterogeneity, allowing genotype ‐ phenotype correlations for both genes and providing insights into structure ‐ function relationships for the NPC1 protein.
Journal ArticleDOI
SphK1 and SphK2, Sphingosine Kinase Isoenzymes with Opposing Functions in Sphingolipid Metabolism
Michael Maceyka,Heidi Sankala,Nitai C. Hait,Hervé Le Stunff,Hong Liu,Rachelle E. Toman,Claiborne Lee Collier,Min Zhang,Leslie S. Satin,Alfred H. Merrill,Sheldon Milstien,Sarah Spiegel +11 more
TL;DR: The results demonstrate that SphK1 and SphK2 have opposing roles in the regulation of ceramide biosynthesis and suggest that the location of sphingosine 1-phosphate production dictates its functions.
Journal Article
[Niemann-Pick disease type C].
TL;DR: Niemann-Pick disease type C is an autosomal recessive neurovisceral lipid storage disorder, but the basic defect has not yet been clarified, and many therapies, i.e. dimethyl sulfoxide, low-cholesterol diet and transplantations, have been challenged but improvement of neurological symptoms have not been reported.
Journal ArticleDOI
Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study.
TL;DR: This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit, and miglustat improves or stabilises several clinically relevant markers of NPC.
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