Hyun Lee1,2,*, Jong Kil Lee1,3,4,*, Min Hee Park1,3,4, Yu Ri Hong1,2, Hugo H. Marti5, Hyongbum Kim6, Yohei Okada7, Makoto Otsu8, Eul-Ju Seo9, Jae-Hyung Park10, Jae-Hoon Bae10, Nozomu Okino11, Xingxuan He12, Edward H. Schuchman12, Jae-sung Bae1,3,4 & Hee Kyung Jin1,2
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. 3 Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-842, Korea. 4 Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 700-842, Korea. 5 Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg 69120, Germany. 6 Graduate School of Biomedical Science and Engineering/College of Medicine, Hanyang University, Seoul 133-791, Korea. 7 Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan. 8 Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. 9 Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea. 10 Department of Physiology, School of Medicine, Keimyung University, Daegu 704-701, Korea. 11 Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 812-8581, Japan. 12 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
* These authors contributed equally to this work.
Correspondence to: Jae-sung Bae or Hee Kyung Jin
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.