| First Author | Lee H | Year | 2014 |
| Journal | Nat Commun | Volume | 5 |
| Pages | 5514 | PubMed ID | 25417698 |
| Mgi Jnum | J:281260 | Mgi Id | MGI:6210668 |
| Doi | 10.1038/ncomms6514 | Citation | Lee H, et al. (2014) Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons. Nat Commun 5:5514 |
| abstractText | 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. |
