Hyun Lee 1 , 2 , Jong Kil Lee 1 , 3 , 4 , Min Hee Park 1 , 3 , 4 , Yu Ri Hong 1 , 2 , Hugo H. Marti 5 , Hyongbum Kim 6 , Yohei Okada 7 , Makoto Otsu 8 , Eul-Ju Seo 9 , Jae-Hyung Park 10 , Jae-Hoon Bae 10 , Nozomu Okino 11 , Xingxuan He 12 , Edward H. Schuchman 12 , Jae-sung Bae a , 1 , 3 , 4 , Hee Kyung Jin b , 1 , 2
24 November 2014
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.
Sphingosine is abnormally accumulated in Niemann–Pick type C disease (NP–C), but the causes of this accumulation have not been fully characterized. Here the authors show that sphingosine kinase activity is reduced in NP–C patient fibroblasts and NP–C mouse neurons due to defective vascular endothelial growth factor levels, suggesting therapeutic avenues.