@article{bd794accb3154f5a8c53b239d10b353f,
title = "Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes",
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 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.",
keywords = "CERS2, ceramide, demyelination, lipid, microglia, myelin, sphingolipid",
author = "Teo, {Jonathan D.} and Marian, {Oana C.} and Spiteri, {Alanna G.} and Madeline Nicholson and Huitong Song and Khor, {Jasmine X.Y.} and McEwen, {Holly P.} and Anjie Ge and Sen, {Monokesh K.} and Laura Piccio and Fletcher, {Jessica L.} and King, {Nicholas J.C.} and Murray, {Simon S.} and Br{\"u}ning, {Jens C.} and Don, {Anthony S.}",
note = "Funding Information: This research was supported by project grant APP1100626 and Ideas grant APP2002660 (A.S.D.) from the National Health and Medical Research Council (NHMRC), Australia; project grant 20-0113 from MS Research Australia (A.S.D. and L.P.); and an Australian government Research Training Stipend (O.C.M.). We gratefully acknowledge subsidized access to the Sydney Mass Spectrometry, Sydney Cytometry, and Sydney Microscopy and Microanalysis core facilities, and subsidized mouse housing provided by Laboratory Animal Services, University of Sydney. Transmission electron microscopy sample preparation and imaging was performed at the Centre for Advanced Histology and Microscopy, Peter MacCallum Cancer Centre, Melbourne. The corresponding author is very grateful to Dr Yael Pewzner-Jung and Prof Anthony Futerman from the Weizmann Institute, Israel, for providing tissue samples from CerS2 knockout mice that triggered the initiation of this project. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians. Funding Information: This research was supported by project grant APP1100626 and Ideas grant APP2002660 (A.S.D.) from the National Health and Medical Research Council (NHMRC), Australia; project grant 20‐0113 from MS Research Australia (A.S.D. and L.P.); and an Australian government Research Training Stipend (O.C.M.). We gratefully acknowledge subsidized access to the Sydney Mass Spectrometry, Sydney Cytometry, and Sydney Microscopy and Microanalysis core facilities, and subsidized mouse housing provided by Laboratory Animal Services, University of Sydney. Transmission electron microscopy sample preparation and imaging was performed at the Centre for Advanced Histology and Microscopy, Peter MacCallum Cancer Centre, Melbourne. The corresponding author is very grateful to Dr Yael Pewzner‐Jung and Prof Anthony Futerman from the Weizmann Institute, Israel, for providing tissue samples from CerS2 knockout mice that triggered the initiation of this project. Open access publishing facilitated by The University of Sydney, as part of the Wiley ‐ The University of Sydney agreement via the Council of Australian University Librarians. Publisher Copyright: {\textcopyright} 2022 The Authors. GLIA published by Wiley Periodicals LLC.",
year = "2022",
doi = "10.1002/glia.24329",
language = "English",
volume = "71",
pages = "1120--1141",
journal = "GLIA",
issn = "0894-1491",
number = "4",
}