Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons
- Title
- Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons
- Other Titles
- SphK pathway in Niemann-Pick type C neurons
- Author
- 김형범
- Keywords
- Cell signalling; Lipid-storage diseases; Medical research; Pathogenesis
- Issue Date
- 2014-11
- Publisher
- Nature Publishing Group
- Citation
- Nature Communications, 2014, 5, P.5514
- 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.
- URI
- https://www.nature.com/articles/ncomms6514http://hdl.handle.net/20.500.11754/54343
- ISSN
- 2041-1723
- DOI
- 10.1038/ncomms6514
- Appears in Collections:
- GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > ETC
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