Biology subjects

Teo, J. D.

Publications and source records attributed to Teo, J. D..

5 recordsLinked to original sources

bioRxiv2026

In vivo deuteration reveals pronounced variation in myelin lipid turnover rates and reduced myelin renewal with ageing

Myelin turnover is essential for its structural and functional integrity, yet how this particularly lipid-rich membrane is renewed and why it deteriorates with ageing remain unresolved. Combining deuterium oxide administration in mice with high resolution lipidomics, we establish that brain lipid turnover rates are highly heterogeneous, differ by brain region, and depend primarily on lipid class. Half-lives of common glycerophospholipids in purified myelin were under 2 months whereas many sphingolipids exhibited half-lives exceeding 8 months, dependent on acyl chain length and saturation. Myelin sphingolipid and cholesterol replacement rates in the corpus callosum decreased markedly between 3 and 12 months of age, while disrupting lipid trafficking through ApoE ablation preferentially impaired cholesterol turnover and incorporation into myelin. Our results establish that myelin renewal occurs through continual replacement of individual lipid constituents in a manner that depends on lipid class, hydrophobicity, and ApoE-dependent trafficking, and that this process slows significantly with ageing.

biochemistry↗

bioRxiv2025

Quantification and Localisation of New Brain Lipid Synthesis Using Deuterium Oxide and High Resolution Mass Spectrometry

Myelin is the lipid-rich membrane that surrounds neuronal axons and is essential for neurological function in vertebrates. The development of therapeutics that stimulate myelin repair to treat demyelinating disorders such as multiple sclerosis is hampered by the inability to distinguish newly-synthesised from pre-existing myelin. This study aimed to develop a method to quantify and localise new myelin lipid synthesis in vivo. Deuterium oxide was administered for two weeks in the drinking water of mice fed normal chow, chow containing the demyelinating toxin cuprizone, or during spontaneous remyelination following cuprizone withdrawal. Liquid chromatography-tandem mass spectrometry and mass spectrometry imaging were used to quantify and localise the newly synthesised, deuterated lipids. While most glycerophospholipids were constitutively deuterated, deuteration of myelin-enriched sulfatides, hexosylceramides, and phosphatidylethanolamine plasmalogens was only apparent during remyelination. Deuterated hexosylceramide and phosphatidylethanolamine plasmalogen species were localised primarily to the corpus callosum, the white matter tract that is most heavily affected by cuprizone. Most deuterium atoms were found in the fatty acyl chains, indicative of de novo lipid synthesis. These methods provide the means to quantify and spatially profile dynamic lipid synthesis across diverse biological contexts, including understanding myelin homeostasis and preclinical evaluation of remyelinating therapeutics.

biochemistry↗

bioRxiv2022

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

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

neuroscience↗

bioRxiv2021

Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication

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 ageing in SphK2-/- compared to WT mice. These results provide the first evidence that SphK2, the dominant enzyme catalysing S1P synthesis in the adult brain, is essential for remyelination following a demyelinating insult and myelin maintenance with ageing. We propose that persistently high levels of sphingosine and ceramide, a direct consequence of SphK2 deficiency, may block remyelination. Table of Contents Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/431183v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@e01edcorg.highwire.dtl.DTLVardef@9fdf6org.highwire.dtl.DTLVardef@6012org.highwire.dtl.DTLVardef@a3513b_HPS_FORMAT_FIGEXP M_FIG C_FIG Main PointsO_LIThe lipid kinase sphingosine kinase 2 (SphK2) is essential for remyelination following a demyelinating insult (cuprizone). C_LIO_LISphK2 protects against cuprizone-mediated oligodendrocyte loss. C_LIO_LISphK2 deficiency leads to thinner myelin with ageing. C_LI

neuroscience↗

bioRxiv2020

A novel function of sphingosine kinase 2 in the metabolism of sphinga-4,14-diene lipids.

The number, position, and configuration of double bonds in lipid acyl chains affects membrane packing, fluidity, and recruitment of signalling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Sphingolipids with a diunsaturated sphingadiene base have been reported but are poorly characterised. Employing high-resolution untargeted mass spectrometry, we observed marked accumulation of lipids containing a sphingadiene base, but not those with a more common sphingosine backbone, in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). Applying ultraviolet photodissociation tandem mass spectrometry (UVPD-MS/MS) the double bonds were confidently assigned to the C4-C5 and C14-C15 positions of the sphingoid base. Sphingosine kinases are involved in lysosomal catabolism of all sphingolipids, producing sphingoid base phosphates that are irreversibly degraded by sphingosine 1-phosphate lyase. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments demonstrated that ceramides with a sphingosine base are more rapidly metabolised in cultured cells than those with a sphingadiene base. SphK2 silencing significantly impeded the catabolism of both sphingosine- and sphingadiene-based sphingolipids. Since SphK2 is the dominant sphingosine kinase in brain, we propose that accumulation of sphingadiene lipids in SphK2-deficient brains results from the intrinsically slower catabolism of sphingadiene lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We speculate that accumulation of these lipids in the absence of SphK2 function may affect the fluidity and signalling properties of cell membranes.

biochemistry↗