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Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism

  • Niemann–Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions of Npc1−/− mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we Int. J. Mol. Sci. 2020, 21, 4502; doi:10.3390/ijms21124502 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 4502 2 of 31 studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1−/− mice in all brain regions, together with distinct changes in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1−/− mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable

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Author: Anne Gläser, Franziska Hammerl, Markus H. Gräler, Sina M. Coldewey, Christin Völkner, Moritz J. Frech, Fan Yang, Jiankai Luo, Eric Tönnies, Oliver von Bohlen und Halbach, Nicola Brandt, Diana Heimes, Anna-Maria Neßlauer, Georg Christoph Korenke, Marta Owczarek-Lipska, John Neidhardt, Arndt Rolfs, Andreas Wree, Martin Witt, Anja Ursula Bräuer
URN:urn:nbn:de:gbv:9-opus-64859
DOI:https://doi.org/10.3390/ijms21124502
ISSN:1422-0067
Parent Title (English):International Journal of Molecular Sciences
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Date of first Publication:2020/06/24
Release Date:2022/11/22
Tag:HPTLC; Niemann–Pick disease type C1; S1P; brain; fibroblasts; mass spectrometry; qRT-PCR; sphingolipids; sphingosine-1-phosphate receptors; white matter
GND Keyword:-
Volume:21
Issue:12
Page Number:31
Faculties:Universitätsmedizin / Institut für Anatomie und Zellbiologie
Licence (German):License LogoCreative Commons - Namensnennung