Pathological roles of the VEGF/SphK pathway in Niemann-Pick type Cneurons
| Autor: | Jae-Hoon Bae, Xingxuan He, Jong Kil Lee, Eul Ju Seo, Edward H. Schuchman, Nozomu Okino, Yu Ri Hong, Makoto Otsu, Jae-sung Bae, Hyongbum Kim, Hyun Lee, Jae Hyung Park, Yohei Okada, Hugo H. Marti, Hee Kyung Jin, Min Hee Park |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Pyridines Induced Pluripotent Stem Cells Sphingosine kinase General Physics and Astronomy Bone Marrow Cells Mice Transgenic Mice SCID Biology Article General Biochemistry Genetics and Molecular Biology Cell Line Mice Purkinje Cells chemistry.chemical_compound Niemann-Pick C1 Protein Sphingosine Autophagy medicine Animals Humans RNA Small Interfering Induced pluripotent stem cell Protein Kinase Inhibitors Adaptor Proteins Signal Transducing Mice Inbred BALB C Membrane Glycoproteins Multidisciplinary Niemann–Pick disease type C Intracellular Signaling Peptides and Proteins Mesenchymal Stem Cells Niemann-Pick Disease Type C Kinase insert domain receptor General Chemistry medicine.disease Vascular Endothelial Growth Factor Receptor-2 Microspheres Cell biology Vascular endothelial growth factor Vascular endothelial growth factor A chemistry Cell culture Phthalazines RNA Interference Carrier Proteins |
| Zdroj: | NATURE COMMUNICATIONS(5) Nature Communications |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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