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

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 Schuchman; Jae-Sung Bae; Hee Kyung Jin

doi:10.1038/ncomms6514

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

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

Authors

Hyun Lee¹, Jong Kil Lee², Min Hee Park², Yu Ri Hong¹, Hugo H Marti³, Hyongbum Kim⁴, Yohei Okada⁵, Makoto Otsu⁶, Eul-Ju Seo⁷, Jae-Hyung Park⁸, Jae-Hoon Bae⁸, Nozomu Okino⁹, Xingxuan He¹⁰, Edward H Schuchman¹⁰, Jae-Sung Bae², Hee Kyung Jin¹

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.

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
Intracellular Signaling Peptides and Proteins
Male
Membrane Glycoproteins / genetics*
Mesenchymal Stem Cells / cytology
Mesenchymal Stem Cells / metabolism
Mice
Mice, Inbred BALB C
Mice, SCID
Mice, Transgenic
Microspheres
Niemann-Pick C1 Protein
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
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins
NPC1 protein, human
Niemann-Pick C1 Protein
Phthalazines
Protein Kinase Inhibitors
Pyridines
RNA, Small Interfering
SPHKAP protein, human
VEGFA protein, human
Vascular Endothelial Growth Factor A
vatalanib
Kdr protein, mouse
Vascular Endothelial Growth Factor Receptor-2
Sphingosine

Grants and funding

R37 HD028607/HD/NICHD NIH HHS/United States