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

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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	5514
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6514
State	Published - 2014

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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.",

author = "Hyun Lee and Lee, {Jong Kil} and Park, {Min Hee} and Hong, {Yu Ri} and Marti, {Hugo H.} and Hyongbum Kim and Yohei Okada and Makoto Otsu and Seo, {Eul Ju} and Park, {Jae Hyung} and Bae, {Jae Hoon} and Nozomu Okino and Xingxuan He and Schuchman, {Edward H.} and Bae, {Jae Sung} and Jin, {Hee Kyung}",

year = "2014",

doi = "10.1038/ncomms6514",

language = "English",

volume = "5",

journal = "Nature Communications",

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T1 - Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons

AU - Lee, Hyun

AU - Lee, Jong Kil

AU - Park, Min Hee

AU - Hong, Yu Ri

AU - Marti, Hugo H.

AU - Kim, Hyongbum

AU - Okada, Yohei

AU - Otsu, Makoto

AU - Seo, Eul Ju

AU - Park, Jae Hyung

AU - Bae, Jae Hoon

AU - Okino, Nozomu

AU - He, Xingxuan

AU - Schuchman, Edward H.

AU - Bae, Jae Sung

AU - Jin, Hee Kyung

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

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

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