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

  • Nat Commun. 2014 Nov 24;5:5514. doi: 10.1038/ncomms6514.
Hyun Lee  1 ,  Jong Kil Lee  2 ,  Min Hee Park  2 ,  Yu Ri Hong  1 ,  Hugo H Marti  3 ,  Hyongbum Kim  4 ,  Yohei Okada  5 ,  Makoto Otsu  6 ,  Eul-Ju Seo  7 ,  Jae-Hyung Park  8 ,  Jae-Hoon Bae  8 ,  Nozomu Okino  9 ,  Xingxuan He  10 ,  Edward H Schuchman  10 ,  Jae-Sung Bae  2 ,  Hee Kyung Jin  1
Affiliations
  • 1. 1] Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu 702-701, Korea [2] Department of Laboratory Animal Medicine, Cell and Matrix Research Institute, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea.
  • 2. 1] Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu 702-701, Korea [2] Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-842, Korea [3] Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 700-842, Korea.
  • 3. Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg 69120, Germany.
  • 4. Graduate School of Biomedical Science and Engineering/College of Medicine, Hanyang University, Seoul 133-791, Korea.
  • 5. Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
  • 6. Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
  • 7. Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.
  • 8. Department of Physiology, School of Medicine, Keimyung University, Daegu 704-701, Korea.
  • 9. Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 812-8581, Japan.
  • 10. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
PMID: 25417698 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.