Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication

Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1002/glia.24074
Journal or Publication Title: Glia
Date: 16 August 2021
Divisions: Lipid Metabolism and Neurochemistry
Depositing User: General Admin
Identification Number: 10.1002/glia.24074
ISSN: 0894-1491
Date Deposited: 10 Oct 2021 10:46

Therapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases. Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through five G-protein coupled receptors. S1P receptor agonists such as Fingolimod are valuable immunosuppressants used to treat multiple sclerosis, and promote oligodendrocyte survival. However, the role for endogenous S1P, synthesized by the enzyme sphingosine kinase 2 (SphK2), in oligodendrocyte survival and myelination has not been established. This study investigated the requirement for SphK2 in oligodendrocyte survival and remyelination using the cuprizone mouse model of acute demyelination, followed by spontaneous remyelination. Oligodendrocyte density did not differ between untreated wild-type (WT) and SphK2 knockout (SphK2-/- ) mice. However, cuprizone treatment caused significantly greater loss of mature oligodendrocytes in SphK2-/- compared to WT mice. Following cuprizone withdrawal, spontaneous remyelination occurred in WT but not SphK2-/- mice, even though progenitor and mature oligodendrocyte density increased in both genotypes. Levels of cytotoxic sphingosine and ceramide were higher in the corpus callosum of SphK2-/- mice, and in contrast to WT mice, did not decline following cuprizone withdrawal in SphK2-/- mice. We also observed a significant reduction in myelin thickness with aging in SphK2-/- compared to WT mice. These results provide the first evidence that SphK2, the dominant enzyme catalyzing S1P synthesis in the adult brain, is essential for remyelination following a demyelinating insult and myelin maintenance with aging. We propose that persistently high levels of sphingosine and ceramide, a direct consequence of SphK2 deficiency, may block remyelination.

Keywords: S1P; SPHK2; multiple sclerosis; myelin; remyelination; sphingosine 1-phosphate; sphingosine kinase.

Song, Huitong
McEwen, Holly P.
Duncan, Thomas
Lee, Jun Yup
Teo, Jonathan D.
Don, Anthony S.
Last Modified: 10 Oct 2021 10:46
URI: https://eprints.centenary.org.au/id/eprint/1079

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