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)...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
24 November 2014
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| In: |
Nature Communications
Year: 2014, Volume: 5 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms6514 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/ncomms6514 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/ncomms6514 
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| Author Notes: | Hyun Lee, Jong Kil Lee, Min Hee Park, Yu Ri Hong, Hugo H. Marti, Hyongbum Kim, Yohei Okada, Makoto Otsu, Eul-Ju Seo, Jae-Hyung Park, Jae-Hoon Bae, Nozomu Okino, Xingxuan He, Edward H. Schuchman, Jae-sung Bae & Hee Kyung Jin |
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| 520 | |a 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. | ||
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