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

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Author(s)
Hyun LeeJong Kil LeeMin Hee ParkYu Ri HongHugo H. MartiHyongbum KimYohei OkadaMakoto OtsuEul-Ju SeoJae-Hyung ParkJae-Hoon BaeNozomu OkinoXingxuan HeEdward H. SchuchmanJae-sung BaeHee Kyung Jin
Keimyung Author(s)
Park, Jae HyungBae, Jae Hoon
Department
Dept. of Physiology (생리학)
Journal Title
Nature Communication
Issued Date
2014
Volume
5
Issue
5514
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.
Keimyung Author(s)(Kor)
박재형
배재훈
Publisher
School of Medicine
Citation
Hyun Lee et al. (2014). Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons. Nature Communication, 5(5514), 1–17. doi: 10.1038/ncomms6514
Type
Article
ISSN
2041-1723
DOI
10.1038/ncomms6514
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/33471
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
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