The myelin sheaths that surround neuronal axons facilitate efficient neurological signal transmission and are essential for neurological function. Myelin is comprised 70-80% of lipids and undergoes continuous turnover to sustain its structural integrity. This turnover involves the coordinated synthesis, transport and degradation of lipids. These processes cannot be resolved by quantifying lipids at discrete time points.
This study introduces a new method to track brain lipid turnover, by administering deuterium oxide in the drinking water to label newly synthesised brain lipids in mice. High-resolution liquid chromatography-tandem mass spectrometry was employed to quantify deuterium incorporation into a broad range of lipids (~150 lipids) from cortex, corpus callosum, and biochemically-isolated myelin. Lipid turnover rates were determined after developmental myelin labelling, by following the decline in deuteration levels over a 10-month turnover period without deuterium oxide. In the reverse approach, 8 weeks of deuterium labelling was commenced at 3 and 12 months of age, to quantify new lipid synthesis.
These complementary approaches revealed tremendous heterogeneity in turnover rates for different myelin lipid components. Myelin-specific glycosphingolipids (hexosylceramides and sulfatides) demonstrated very long half-lives (< 4 months), with only 10% of the lipid pool replaced in 8 weeks. In contrast, over 90% of common cellular glycerophospholipids (phosphatidylcholine, phosphatidylethanolomine, e.t.c.) were replaced within 8 weeks (turnover < 2 months), even in isolated myelin. Turnover rates for long-lived glycosphingolipids varied as a function of lipid acyl chain length and saturation state, indicating that myelin lipid turnover is dependent on the fluidity of the individual lipid species within the membrane environment. Our novel data therefore suggests a new paradigm for myelin turnover, whereby fluidity of lipid components within the membrane affects their incorporation into membrane vesicles that are destined for degradation. This improved understanding is important in the new therapeutic frontier of myelin repair for neurodegenerative diseases.