Blog
About

23
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Pathological roles of the VEGF/SphK pathway in Niemann–Pick type C neurons

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Sphingosine is a major storage compound in Niemann–Pick type C disease (NP–C), although the pathological role(s) of this accumulation have not been fully characterized. Here we found that sphingosine kinase (SphK) activity is reduced in NP–C patient fibroblasts and NP–C mouse Purkinje neurons (PNs) due to defective vascular endothelial growth factor (VEGF) levels. Sphingosine accumulation due to inactivation of VEGF/SphK pathway led to PNs loss via inhibition of autophagosome–lysosome fusion in NP–C mice. VEGF activates SphK by binding to VEGFR2, resulting in decreased sphingosine storage as well as improved PNs survival and clinical outcomes in NP–C cells and mice. We also show that induced pluripotent stem cell (iPSC)-derived human NP–C neurons are generated and the abnormalities caused by VEGF/SphK inactivity in these cells are corrected by replenishment of VEGF. Overall, these results reveal a pathogenic mechanism in NP–C neurons where defective SphK activity is due to impaired VEGF levels.

          Abstract

          Sphingosine is abnormally accumulated in Niemann–Pick type C disease (NP–C), but the causes of this accumulation have not been fully characterized. Here the authors show that sphingosine kinase activity is reduced in NP–C patient fibroblasts and NP–C mouse neurons due to defective vascular endothelial growth factor levels, suggesting therapeutic avenues.

          Related collections

          Most cited references 30

          • Record: found
          • Abstract: found
          • Article: not found

          Angiogenesis in cancer, vascular, rheumatoid and other disease.

           J Folkman (1994)
          Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Biodegradable nanoparticles for drug and gene delivery to cells and tissue.

            Biodegradable nanoparticles formulated from poly (D,L-lactide-co-glycolide) (PLGA) have been extensively investigated for sustained and targeted/localized delivery of different agents including plasmid DNA, proteins and peptides and low molecular weight compounds. Research about the mechanism of intracellular uptake of nanoparticles, their trafficking and sorting into different intracellular compartments, and the mechanism of enhanced therapeutic efficacy of nanoparticle-encapsulated agent at cellular level is more recent and is the primary focus of the review. Recent studies in our laboratory demonstrated rapid escape of PLGA nanoparticles from the endo-lysosomal compartment into cytosol following their uptake. Based on the above mechanism, various potential applications of nanoparticles for delivery of therapeutic agents to the cells and tissue are discussed.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Sphingosine-1-phosphate: an enigmatic signalling lipid.

              The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.
                Bookmark

                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                24 November 2014
                : 5
                Affiliations
                [1 ]Stem Cell Neuroplasticity Research Group, Kyungpook National University , Daegu 702-701, Korea
                [2 ]Department of Laboratory Animal Medicine, Cell and Matrix Research Institute, College of Veterinary Medicine, Kyungpook National University , Daegu 702-701, Korea
                [3 ]Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University , Daegu 700-842, Korea
                [4 ]Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-842, Korea
                [5 ]Institute of Physiology and Pathophysiology, University of Heidelberg , Heidelberg 69120, Germany
                [6 ]Graduate School of Biomedical Science and Engineering/College of Medicine, Hanyang University , Seoul 133-791, Korea
                [7 ]Department of Physiology, School of Medicine, Keio University , Tokyo 160-8582, Japan
                [8 ]Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo , Tokyo 108-8639, Japan
                [9 ]Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul 138-736, Korea
                [10 ]Department of Physiology, School of Medicine, Keimyung University , Daegu 704-701, Korea
                [11 ]Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University , Fukuoka 812-8581, Japan
                [12 ]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, USA
                Author notes
                [*]

                These authors contributed equally to this work

                Article
                ncomms6514
                10.1038/ncomms6514
                4263144
                25417698
                Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                Categories
                Article

                Uncategorized

                Comments

                Comment on this article