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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Partial blockage of sterol biosynthesis with a squalene synthase inhibitor in early postnatal Niemann-Pick type C npcnih null mice brains reduces neuronal cholesterol accumulation, abrogates astrogliosis, but may inhibit myelin maturation
Patrick C. Reid,Song Lin,Marie T. Vanier,Yoshiko Ohno-Iwashita,H. James Harwood,William F. Hickey,Catherine C.Y. Chang,Ta-Yuan Chang +7 more
TL;DR: The results show that treating 8-day-old NPC1-/- mice with CP-340868 for 6 days significantly inhibits cholesterol biosynthesis in the mice brains, and reduces neuronal cholesterol accumulation, reduces GM3 ganglioside accumulation, and diminishes astrogliosis in the brain.
Journal ArticleDOI
Establishment and characterization of immortalized Schwann cells from murine model of Niemann-Pick disease type C (spm/spm).
Kazuhiko Watabe,Hiroyuki Ida,Keiko Uehara,Kiyomitsu Oyanagi,Tsuyoshi Sakamoto,Junichi Tanaka,William S. Garver,Shigeki Miyawaki,Kousaku Ohno,Yoshikatsu Eto +9 more
TL;DR: The treatment with an inhibitor of ceramide-specific glucosyltransferase, N-butyldeoxynojirimysin (NB-DNJ) markedly reduced the intracytoplasmic granular immunofluorescence for GM2 ganglioside in SPMS9 cells, whereas the amount of filipin-positive granules remained unchanged.
Journal ArticleDOI
Overexpression of the cholesterol-binding protein MLN64 induces liver damage in the mouse
Juan E. Tichauer,María Gabriela Morales,Ludwig Amigo,Leopoldo Galdames,Andrés D. Klein,Verónica Quiñones,Carla Ferrada,Alejandra Alvarez R,Marie-Christine Rio,Juan Francisco Miquel,Attilio Rigotti,Silvana Zanlungo +11 more
TL;DR: Hepatic MLN64 over-expression induced damage and apoptosis in murine livers and altered cholesterol metabolism is found in mice with chenodeoxycholic acid-induced liver damage.
Journal ArticleDOI
Clues to NPC1-mediated cholesterol export from lysosomes
TL;DR: A 3D structural model of NPC1 is presented, which provides important new clues to the mechanisms by which cholesterol is exported from lysosomes and the mechanism by which Ebola virus docks on the internal surface of the lysOSome-limiting membrane as part of the infection process.
Journal ArticleDOI
Neuronal gene repression in Niemann-Pick type C models is mediated by the c-Abl/HDAC2 signaling pathway.
Pablo Contreras,Marcelo Gonzalez-Zuñiga,Lila González-Hódar,María José Yañez,Andrés E. Dulcey,Juan J. Marugan,Edward Seto,Alejandra R. Alvarez,Silvana Zanlungo +8 more
TL;DR: It is demonstrated that c-Abl activity increases HDAC2 levels inducing neuronal gene repression of key synaptic genes in NPC models, and the involvement of the c- abl/HDAC2 signaling pathway in the regulation of neuronal gene expression in NPC neuronal models is shown.
References
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Book
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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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