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@article{1738277,
author = {Newton, J. and Palladino, E. N. D. and Weigel, C. and Maceyka, M. and Graler, M. H. and Senkal, C. E. and Enriz, R. D. and Marvanová, Pavlína and Jampilek, J. and Lima, S. and Milstien, S. and Spiegel, S.},
article_location = {Bethesda, USA},
article_number = {27},
doi = {http://dx.doi.org/10.1074/jbc.RA120.012659},
keywords = {sphingosine kinase; cholesterol; Niemann?Pick type C; sphingolipids; lysosomal storage disease; genetic disorder; lipid metabolism; neurodegeneration; sphingolipid; sphingosine kinase (SphK); sphingosine-1-phosphate (S1P); NPC1},
language = {eng},
issn = {0021-9258},
journal = {Journal of Biological Chemistry},
title = {Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation},
url = {https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub},
volume = {295},
year = {2020}
}
TY - JOUR
ID - 1738277
AU - Newton, J. - Palladino, E. N. D. - Weigel, C. - Maceyka, M. - Graler, M. H. - Senkal, C. E. - Enriz, R. D. - Marvanová, Pavlína - Jampilek, J. - Lima, S. - Milstien, S. - Spiegel, S.
PY - 2020
TI - Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation
JF - Journal of Biological Chemistry
VL - 295
IS - 27
SP - 9121-9133
EP - 9121-9133
PB - Amer. Soc. Biochem. Mol. Biol.
SN - 00219258
KW - sphingosine kinase
KW - cholesterol
KW - Niemann?Pick type C
KW - sphingolipids
KW - lysosomal storage disease
KW - genetic disorder
KW - lipid metabolism
KW - neurodegeneration
KW - sphingolipid
KW - sphingosine kinase (SphK)
KW - sphingosine-1-phosphate (S1P)
KW - NPC1
UR - https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub
L2 - https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub
N2 - Niemann?Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.
ER -
NEWTON, J., E. N. D. PALLADINO, C. WEIGEL, M. MACEYKA, M. H. GRALER, C. E. SENKAL, R. D. ENRIZ, Pavlína MARVANOVÁ, J. JAMPILEK, S. LIMA, S. MILSTIEN and S. SPIEGEL. Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation. \textit{Journal of Biological Chemistry}. Bethesda, USA: Amer. Soc. Biochem. Mol. Biol., 2020, vol.~295, No~27, p.~9121-9133. ISSN~0021-9258. Available from: https://dx.doi.org/10.1074/jbc.RA120.012659.
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