Nature Communications 2014-01-01

Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons.

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

Index: Nat. Commun. 5 , 5514, (2014)

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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.