RT Journal Article SR Electronic T1 Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.05.29.493337 DO 10.1101/2022.05.29.493337 A1 Jonathan D Teo A1 Oana C Marian A1 Alanna G Spiteri A1 Madeline Nicholson A1 Huitong Song A1 Jasmine XY Khor A1 Holly P McEwen A1 Laura Piccio A1 Jessica L Fletcher A1 Nicholas JC King A1 Simon S Murray A1 Jens C Brüning A1 Anthony S Don YR 2022 UL http://biorxiv.org/content/early/2022/06/08/2022.05.29.493337.abstract AB 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 (CerS2ΔO/ΔO). At 6 weeks of age, normal-appearing myelin had formed in CerS2ΔO/ΔO mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2ΔO/ΔO 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 CerS2ΔO/ΔO mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2ΔO/ΔO mice. By 16 weeks, CerS2ΔO/ΔO mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2ΔO/ΔO 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 PointsOligodendrocytes lacking CerS2 produce myelin using sphingolipids with C16/C18 instead of C22/C24 N-acyl chainsC22/C24 myelin sphingolipids are essential for myelin stability, microglial quiescence, and survival beyond young adulthoodCompeting Interest StatementThe authors have declared no competing interest.