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

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Affiliated Author(s)
박재형배재훈
Alternative Author(s)
Park, Jae HyungBae, Jae Hoon
Journal Title
Nature Communication
ISSN
2041-1723
Issued Date
2014
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.
Department
Dept. of Physiology (생리학)
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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