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

Nat Commun. 2014 Nov 24;5:5514. doi: 10.1038/ncomms6514.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy / genetics
  • Bone Marrow Cells / cytology
  • Carrier Proteins / genetics*
  • Cell Line
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Membrane Glycoproteins / genetics*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Mice, Transgenic
  • Microspheres
  • Niemann-Pick Disease, Type C / genetics*
  • Phthalazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Purkinje Cells / metabolism
  • Pyridines / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • Sphingosine
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Phthalazines
  • Protein Kinase Inhibitors
  • Pyridines
  • RNA, Small Interfering
  • SKIP protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vatalanib
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2
  • Sphingosine