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
Citations
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Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein-deficient cells
TL;DR: It is shown here that the requirement for NPC1 is decreased in cells containing lower levels of protein glycosylation, which supports a model in which NPC1 protein helps transfer cholesterol past the glycocalyx barrier that lines the interior of lysosomes.
Journal ArticleDOI
Polyrotaxane-based systemic delivery of β-cyclodextrins for potentiating therapeutic efficacy in a mouse model of Niemann-Pick type C disease
Atsushi Tamura,Nobuhiko Yui +1 more
TL;DR: Analysis of tissue cholesterol revealed that PRX treatment markedly suppressed the tissue accumulation of cholesterol in the NPC mouse model, but did not alter cholesterol content in wild‐type mice, and acid‐labile PRX is therefore a promising candidate for potentiating the efficacy of &bgr;‐CD in the treatment of NPC disease.
Journal ArticleDOI
Regulation of cholesterol homeostasis by liver X receptors
Yan-Wei Hu,Lei Zheng,Qian Wang +2 more
TL;DR: In this review, the important role of LXRs in regulating expression of key members that keep cholesterol levels in balance are summarized.
Journal ArticleDOI
Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function.
Andrey Frolov,Kalpana Srivastava,Dorit Daphna-Iken,Linton M. Traub,Jean E. Schaffer,Daniel S. Ory +5 more
TL;DR: It is demonstrated that low-density lipoprotein receptor activity is increased 3-fold in the M87 mutant, and likely contributes to accumulation of excess cholesterol, implicate cholesterol overload in the formation of an NPC-like compartment that is independent of inhibition of NPC1 or HE1/NPC2 function.
Journal ArticleDOI
Spatial and temporal distribution of intracellular free cholesterol in brains of a Niemann-Pick type C mouse model showing hyperphosphorylated tau protein. Implications for Alzheimer's disease.
TL;DR: The NPC mouse model may serve as a tool to analyse the role of cholesterol in initial changes of tau that eventually lead to the formation of tangles in both NPC and AD, strengthening the concept that an alteration in cholesterol metabolism may play an important role in AD.
References
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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.
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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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