Reference - Detail
|Author||Lee H, Lee JK, Park MH, Hong YR, Marti HH, Kim H, Okada Y, Otsu M, Seo EJ, Park JH, Bae JH, Okino N, He X, Schuchman EH, Bae JS, Jin HK.|
|Title||Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons.|
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.
|MeSH||Adaptor Proteins, Signal Transducing / metabolism* Animals Autophagy / genetics Bone Marrow Cells / cytology Carrier Proteins / genetics* Cell Line Humans Induced Pluripotent Stem Cells / metabolism Male Membrane Glycoproteins / genetics* Mesenchymal Stem Cells / cytology Mesenchymal Stem Cells / metabolism Mice Mice, Inbred BALB C Mice, SCID Mice, Transgenic Microspheres Niemann-Pick Disease, Type C / genetics* Phthalazines / pharmacology Protein Kinase Inhibitors / pharmacology Purkinje Cells / metabolism Pyridines / pharmacology RNA Interference RNA, Small Interfering Sphingosine Vascular Endothelial Growth Factor A / biosynthesis Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism* Vascular Endothelial Growth Factor A / pharmacology* Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 / genetics Vascular Endothelial Growth Factor Receptor-2 / metabolism|
|WOS Category||BIOCHEMISTRY & MOLECULAR BIOLOGY|
|Human and Animal Cells|