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

Author

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  • Hyun Lee

    (Stem Cell Neuroplasticity Research Group, Kyungpook National University
    Cell and Matrix Research Institute, College of Veterinary Medicine, Kyungpook National University)

  • Jong Kil Lee

    (Stem Cell Neuroplasticity Research Group, Kyungpook National University
    Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
    BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University)

  • Min Hee Park

    (Stem Cell Neuroplasticity Research Group, Kyungpook National University
    Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
    BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University)

  • Yu Ri Hong

    (Stem Cell Neuroplasticity Research Group, Kyungpook National University
    Cell and Matrix Research Institute, College of Veterinary Medicine, Kyungpook National University)

  • Hugo H. Marti

    (Institute of Physiology and Pathophysiology, University of Heidelberg)

  • Hyongbum Kim

    (Graduate School of Biomedical Science and Engineering/College of Medicine, Hanyang University)

  • Yohei Okada

    (School of Medicine, Keio University)

  • Makoto Otsu

    (Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo)

  • Eul-Ju Seo

    (Asan Medical Center, University of Ulsan College of Medicine)

  • Jae-Hyung Park

    (School of Medicine, Keimyung University)

  • Jae-Hoon Bae

    (School of Medicine, Keimyung University)

  • Nozomu Okino

    (Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University)

  • Xingxuan He

    (Icahn School of Medicine at Mount Sinai)

  • Edward H. Schuchman

    (Icahn School of Medicine at Mount Sinai)

  • Jae-sung Bae

    (Stem Cell Neuroplasticity Research Group, Kyungpook National University
    Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
    BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University)

  • Hee Kyung Jin

    (Stem Cell Neuroplasticity Research Group, Kyungpook National University
    Cell and Matrix Research Institute, College of Veterinary Medicine, Kyungpook National University)

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.

Suggested Citation

  • 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. Sch, 2014. "Pathological roles of the VEGF/SphK pathway in Niemann–Pick type C neurons," Nature Communications, Nature, vol. 5(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6514
    DOI: 10.1038/ncomms6514
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