Biology subjects

Michael, J. A.

Publications and source records attributed to Michael, J. A..

4 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↗

bioRxiv2025

Dynamic neutrophil lipidome remodeling during induction of NETosis

Neutrophil Extracellular Trap formation (NETosis) affects a wide variety of clinically relevant human diseases. Although lipid remodeling is essential for neutrophil function and membrane rupture during NETosis, the neutrophil lipidome and its dynamics have not been characterized. Thus, we establish the first quantitative lipidome of human neutrophils comprising 1,039 species across nine orders of magnitude and map its remodeling during NETosis. NET formation caused profound alterations in the phosphatidylinositol, phosphatidic acid, diacylglycerol and lysoglycerophospholipid levels. Calcium- and reactive oxygen species-dependent NETosis pathways displayed distinct lipidomic trajectories, yet converged on the significance of phospholipid lipase networks. Pharmacological inhibition of this networks altered lipid composition and markedly impaired NETosis, while diacylglycerol (DG) treatment revoked the effect. Altogether our findings reveal lipid remodeling as a fundamental determinant of NETosis and identify interconnected and dependent phospholipid lipase networks with downstream DG-dependent signaling as a potential therapeutic target in NET-associated diseases.

molecular biology↗

bioRxiv2023

A High-Throughput Data-Independent Acquisition Workflow for Deep Characterisation of the sn-Isomer Lipidome

We report a workflow based on ozone-induced dissociation for untargeted characterization of hundreds of sn-resolved glycerophospholipid isomers from biological extracts in under 20 minutes, coupled with an automated data analysis pipeline. It provides an order of magnitude increase in the number of sn-isomer pairs identified compared to previous reports, reveals that sn-isomer populations are tightly regulated and significantly different between cell lines, and enables identification of rare lipids containing ultra-long chain monounsaturated acyl chains.

cell biology↗