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
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TLDR
Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.Abstract:
Niemann-Pick type C2 disease (NP-C2) is a fatal hereditary disorder of unknown etiology characterized by defective egress of cholesterol from lysosomes. Here we show that the disease is caused by a deficiency in HE1, a ubiquitously expressed lysosomal protein identified previously as a cholesterol-binding protein. HE1 was undetectable in fibroblasts from NP-C2 patients but present in fibroblasts from unaffected controls and NP-C1 patients. Mutations in the HE1 gene, which maps to chromosome 14q24.3, were found in NP-C2 patients but not in controls. Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.read more
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Journal ArticleDOI
Endosomal/Lysosomal Processing of Gangliosides Affects Neuronal Cholesterol Sequestration in Niemann-Pick Disease Type C
Sharon Zhou,Cristin Davidson,Robert McGlynn,Robert McGlynn,Gloria Stephney,Kostantin Dobrenis,Marie T. Vanier,Steven U. Walkley +7 more
TL;DR: It is shown that NPC2-deficient mice lacking this enzyme also exhibit reduced cholesterol, but that genetically restricting synthesis to only a-series gangliosides fully restores neuronal cholesterol storage to typical disease levels, providing further evidence that NPC1 and NPC2 proteins participate in endosomal/lysosomal processing of both sphingolipids and cholesterol.
Book ChapterDOI
Ganglioside Metabolism in Health and Disease.
TL;DR: Gangliosides (GGs) are cell type-specific sialic acid-containing glycosphingolipids, which are enriched in mammalian brain, and Inherited defects of these transferases affect not only single structures but defined glycolipid series.
Journal ArticleDOI
Before the loss: neuronal dysfunction in Niemann-Pick Type C disease.
TL;DR: Fundamental aspects of neurons that appear to be affected by NPC disease are highlighted, including their morphology, metabolism, intracellular transport, electrical signaling, and response to environmental factors, and suggest other potentially important areas for future investigation.
Journal ArticleDOI
Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells.
Nina H. Pipalia,Kanagaraj Subramanian,Shu Mao,Harold Ralph,Darren M. Hutt,Samantha M. Scott,William E. Balch,Frederick R. Maxfield +7 more
TL;DR: Treatment of patient-derived NPC1I1061T fibroblasts with histone deacetylase inhibitors (HDACis) vorinostat or panobinostat increases expression of the mutant NPC1 protein and leads to correction of the cholesterol storage.
Journal ArticleDOI
Differential regulation of ATP binding cassette protein A1 expression and ApoA-I lipidation by Niemann-Pick type C1 in murine hepatocytes and macrophages.
Ming-Dong Wang,Vivian Franklin,Meenakshi Sundaram,Robert S. Kiss,Kenneth Ho,Michel Gallant,Yves L. Marcel +6 more
TL;DR: The lipidation of endogenously synthesized apoA-I by low density lipoprotein-derived cholesterol or de novo synthesized cholesterol or phospholipids in Npc1-null hepatocytes is significantly increased by about 1, 3, and 8-fold, respectively.
References
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Book
The Metabolic and Molecular Bases of Inherited Disease
TL;DR: In this paper, the authors present a list of disorders of MITOCHONDRIAL FUNCTION, including the following: DISORDERS OF MIOCHONDRIC FERTILITY XIX, XVI, XIX.
Journal ArticleDOI
Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue
TL;DR: The results are shown to favour the ferryl ion structure, or an isomer of this structure, for the higher oxidation state, and theHigher oxidation state may provisionally be named ferrylmyoglobin.
Journal ArticleDOI
Association of Mutations in a Lysosomal Protein with Classical Late-Infantile Neuronal Ceroid Lipofuscinosis
David E. Sleat,Robert J. Donnelly,Henry Lackland,Henry Lackland,Chang Gong Liu,Istvan Sohar,Istvan Sohar,Raju K. Pullarkat,Peter Lobel,Peter Lobel +9 more
TL;DR: In this paper, the mannose 6-phosphate modification of newly synthesized lysosomal enzymes was used as an affinity marker, and a single protein was identified that is absent in LINCL.
Journal ArticleDOI
Niemann–Pick C1 Is a Late Endosome-Resident Protein That Transiently Associates with Lysosomes and the Trans-Golgi Network
TL;DR: Characterizing the subcellular location of the NPC1 protein suggests that U18666A may inhibit the retrograde transport of NPC1 from lysosomes to late endosomes for subsequent transfer to the trans-Golgi network.
Journal Article
Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis.
TL;DR: In this article, the authors conducted a study on skin fibroblast cultures from 32 unrelated Niemann-Pick C patients covering the range of known clinical and biochemical phenotypes.
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