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

Autor: Gläser A; Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany.; Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany., Hammerl F; Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany., Gräler MH; Department of Anaesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany., Coldewey SM; Department of Anaesthesiology and Intensive Care Medicine, Septomics Research Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany., Völkner C; Translational Neurodegeneration Section 'Albrecht Kossel', Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany., Frech MJ; Translational Neurodegeneration Section 'Albrecht Kossel', Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany.; Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany., Yang F; Translational Neurodegeneration Section 'Albrecht Kossel', Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany., Luo J; Translational Neurodegeneration Section 'Albrecht Kossel', Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany.; Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany., Tönnies E; Institute of Anatomy and Cell Biology, University Medicine Greifswald, 17487 Greifswald, Germany., von Bohlen Und Halbach O; Institute of Anatomy and Cell Biology, University Medicine Greifswald, 17487 Greifswald, Germany., Brandt N; Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany., Heimes D; Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany., Neßlauer AM; Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany., Korenke GC; Department of Pediatrics, Klinikum Oldenburg, 26133 Oldenburg, Germany., Owczarek-Lipska M; Human Genetics, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany.; Junior Research Group, Genetics of childhood brain malformations, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany., Neidhardt J; Human Genetics, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany.; Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg,26129 Oldenburg, Germany., Rolfs A; Centogene AG, D-18055 Rostock, Germany., Wree A; Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany., Witt M; Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany., Bräuer AU; Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany.; Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany.; Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg,26129 Oldenburg, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2020 Jun 24; Vol. 21 (12). Date of Electronic Publication: 2020 Jun 24.
DOI: 10.3390/ijms21124502
Abstrakt: 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 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.
Databáze: MEDLINE