Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication

• DOI: 10.1101/2021.02.14.431183
• Publication Date: 2021-02-16T03:20:14Z
• Authors: Huitong Song; Holly P. McEwen; Thomas Duncan; Jun Yup Lee; Jonathan D. Teo; Anthony S. Don
• Keywords: Remyelination; Sphingosine Kinase

Abstract 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 signals through five G-protein coupled receptors. S1P receptor agonists such as Fingolimod valuable immunosuppressants used treat multiple sclerosis, survival. However, the role for endogenous S1P, synthesized by enzyme sphingosine kinase 2 (SphK2), myelination has not been established. This study investigated requirement SphK2 using cuprizone mouse model of acute demyelination, followed spontaneous remyelination. Oligodendrocyte density did differ between untreated wild- type (WT) knockout (SphK2 -/- ) mice. treatment caused significantly greater loss mature oligodendrocytes compared WT Following withdrawal, occurred but mice, even though progenitor increased both genotypes. Levels cytotoxic ceramide were higher corpus callosum contrast decline following withdrawal We also observed a significant reduction myelin thickness with ageing These results provide first evidence SphK2, dominant catalysing synthesis adult brain, insult maintenance ageing. propose persistently high levels ceramide, direct consequence deficiency, may block Table Contents Image Main Points The (SphK2) (cuprizone). protects against cuprizone-mediated loss. deficiency leads thinner