title: Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons.
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.
authors.affiliation: 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.
authors.forename: Hyun
authors.initials: H
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jong Kil
authors.initials: JK
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Min Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Yu Ri
authors.initials: YR
authors.lastname: Hong
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Hugo H
authors.initials: HH
authors.lastname: Marti
authors.affiliation: Graduate School of Biomedical Science and Engineering/College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Hyongbum
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Otsu
authors.affiliation: Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Eul-Ju
authors.initials: EJ
authors.lastname: Seo
authors.affiliation: Department of Physiology, School of Medicine, Keimyung University, Daegu 704-701, Korea.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Physiology, School of Medicine, Keimyung University, Daegu 704-701, Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Bae
authors.affiliation: Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Okino
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Xingxuan
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.affiliation: 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.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Bae
authors.affiliation: 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.
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Jin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D008863:Microspheres; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics*; D010793:Phthalazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011689:Purkinje Cells / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D013110:Sphingosine; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; C466999:SPHKAP protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D013110:Sphingosine