Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes

Teo, J. D.; Mariam, O. C.; Spiteri, A. G.; Nicholson, M.; Song, H.; Khor, J. X.; McEwen, H. P.; Piccio, L.; Fletcher, J.; King, N. J. C.; Murray, S. S.; Brüning, J. C.; Don, A. S.

doi:10.1101/2022.05.29.493337

bioRxiv · 10.1101/2022.05.29.493337

Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes

Teo, J. D.·Mariam, O. C.·Spiteri, A. G.·Nicholson, M.·Song, H.·Khor, J. X.·McEwen, H. P.·Piccio, L.·Fletcher, J.·King, N. J. C.·Murray, S. S.·Brüning, J. C.·Don, A. S.

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Abstract

The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin lipid biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2{Delta}O/{Delta}O). At 6 weeks of age, normal-appearing myelin had formed in CerS2{Delta}O/{Delta}O mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2{Delta}O/{Delta}O mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2{Delta}O/{Delta}O mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2{Delta}O/{Delta}O mice. By 16 weeks, CerS2{Delta}O/{Delta}O mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2{Delta}O/{Delta}O mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases. Main PointsO_LIOligodendrocytes lacking CerS2 produce myelin using sphingolipids with C16/C18 instead of C22/C24 N-acyl chains C_LIO_LIC22/C24 myelin sphingolipids are essential for myelin stability, microglial quiescence, and survival beyond young adulthood C_LI Table of Contents Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/493337v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1125540org.highwire.dtl.DTLVardef@9aeebdorg.highwire.dtl.DTLVardef@1afbeb4org.highwire.dtl.DTLVardef@11156c2_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Teo, J. D., Mariam, O. C., Spiteri, A. G., Nicholson, M., Song, H., Khor, J. X., McEwen, H. P., Piccio, L., Fletcher, J., King, N. J. C., Murray, S. S., Brüning, J. C., Don, A. S.. 2022-05-30. Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes. https://doi.org/10.1101/2022.05.29.493337

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