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

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)...

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Hauptverfasser: Lee, Hyun (VerfasserIn) , Lee, Jong Kil (VerfasserIn) , Park, Min Hee (VerfasserIn) , Hong, Yu Ri (VerfasserIn) , Marti, Hugo (VerfasserIn) , Kim, Hyongbum (VerfasserIn) , Okada, Yohei (VerfasserIn) , Otsu, Makoto (VerfasserIn) , Seo, Eul-Ju (VerfasserIn) , Park, Jae-Hyung (VerfasserIn) , Bae, Jae-Hoon (VerfasserIn) , Okino, Nozomu (VerfasserIn) , He, Xingxuan (VerfasserIn) , Schuchman, Edward H. (VerfasserIn) , Bae, Jae-sung (VerfasserIn) , Jin, Hee Kyung (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 24 November 2014
In: Nature Communications
Year: 2014, Jahrgang: 5
ISSN:2041-1723
DOI:10.1038/ncomms6514
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/ncomms6514
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/ncomms6514
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 11.12.2020
Beschreibung:Online Resource
ISSN:2041-1723
DOI:10.1038/ncomms6514

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