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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NPC1 late endosomes contain elevated levels of non-esterified (‘free’) fatty acids and an abnormally glycosylated form of the NPC2 protein
TL;DR: The results suggest that the function of the NPC2 protein may be compromised as well in NPC1 endosomes, which might explain the paradoxical phenotypic similarities of the two NPC disease complementation groups.
Journal ArticleDOI
Trafficking defects in endogenously synthesized cholesterol in fibroblasts, macrophages, hepatocytes, and glial cells from Niemann-Pick type C1 mice.
TL;DR: It is suggested that endoCHOL may contribute significantly to the overall cholesterol accumulation observed in selective tissues affected by Niemann-Pick type C disease.
Journal ArticleDOI
Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation
Marion Willenborg,Christine Kathrin Schmidt,Peter Braun,Jobst Landgrebe,Kurt von Figura,Paul Saftig,Eeva-Liisa Eskelinen,Eeva-Liisa Eskelinen +7 more
TL;DR: The results suggest that the lysosomal targeting of NPC2 is strictly dependent on MPRs in fibroblasts, although MPR300 seems to be more efficient than MPR46 in the endo/lysosomal compartment.
Journal ArticleDOI
Secretion of sterols and the NPC2 protein from primary astrocytes.
Aino-Liisa Mutka,Sari Lusa,Matts D. Linder,Eija Jokitalo,Outi Kopra,Matti Jauhiainen,Elina Ikonen +6 more
TL;DR: Astrocytes secrete cholesterol in lipoprotein particles but also the cholesterol precursors desmosterol and lathosterol, revealing a complexity of sterol species in astrocytes and bringing up the possibility that some of the effects assigned toAstrocyte cholesterol may be attributed to its penultimate precursor.
Journal ArticleDOI
Chemical screen to reduce sterol accumulation in niemann-pick c disease cells identifies novel lysosomal acid lipase inhibitors
Anton I. Rosenbaum,Madalina Rujoi,Amy Huang,Hong Du,Gregory A. Grabowski,Frederick R. Maxfield +5 more
TL;DR: The utility of phenotypic cellular screens as a means to identify molecular targets for altering a complex process such as intracellular cholesterol trafficking and metabolism is demonstrated.
References
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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
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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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