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.
Highlights
Sphingosine is a major storage compound in Niemann–Pick type C disease (NP–C), the pathological role(s) of this accumulation have not been fully characterized
sphingosine kinase (SphK) was significantly decreased in fibroblasts from NP–C patients compared with normal control fibroblasts (Fig. 1a)
We found that SphK activity and other sphingolipid metabolites in NP–C Purkinje neurons (PNs) were mediated by interactions of bone marrow mesenchymal stem cells (BM-MSCs)-derived vascular endothelial growth factor (VEGF) and its receptor VEGF receptor-2 (VEGFR2) (Fig. 1f; Supplementary Fig. 2e)
Summary
Sphingosine is a major storage compound in Niemann–Pick type C disease (NP–C), the pathological role(s) of this accumulation have not been fully characterized. 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 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. Replenishment of VEGF leads to restoration of SphK activity and improvement of pathology by binding to the VEGF receptor-2 (VEGFR2) in NP– C mice PNs as well as patient-specific cells, preventing sphingosine accumulation, autophagy dysfunction and abnormal calcium homeostasis
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