Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewMetabolism and functions of lipids in myelin☆
Introduction
Myelin is formed by oligodendrocytes and Schwann cells as a lipid-rich and multilamellar structure that encloses segments of axons in the central (CNS) and peripheral nervous systems (PNS) of vertebrates [1], [2], [3], [4], [5], [6]. During the active phase of myelination, these cells generate an enormous amount of lipids in a relatively short period of time. Recent live-imaging analysis of myelination in zebrafish has shown oligodendrocytes (at least in the zebrafish) make new myelin sheaths within a period of just five hours [7]. When myelination is completed, oligodendrocytes have synthesized ~ 40% of the total lipids in the human brain [8]. The abundance of myelin, accounting for ~ 30% of the dry weight of the human brain, and its enrichment in lipids has facilitated its biochemical purification in high yield and purity [9]. Methods used to prepare myelin involve the isolation of myelin membranes by a series of steps that include density gradient centrifugation and differential centrifugation [10]. The isolation procedure is the basis for numerous studies determining the molecular composition of myelin in different species [11], [12], [13], [14], [15], [16], [17]. These studies have shown that the overall ratio of proteins to lipids is around 1 to 186 in myelin [12]. One reason for the enrichment of lipids in myelin is the function of myelin basic protein (MBP) in extruding most proteins from the compacted myelin sheath [18]. While the protein composition differs substantially in PNS and CNS myelin, lipid species are remarkably similar. The quantitatively most significant lipids in myelin are cholesterol, galactosylceramide and ethanolamine plasmalogen. Together, these three lipids comprise for 65% of the total lipid dry weight. Whereas the molar ratio of cholesterol, phospholipids and glycosphingolipids is in most membranes in the order of 25%:65%:10%, the molar ratios in myelin are in the range of 40%:40%:20% [19].
These lipids enable the close packing and tight organization of molecules within the membrane.
Whereas the composition and structural properties of myelin lipids are clearly important to impose stability for the long-term maintenance of myelin, they may also be relevant for our understanding of neurodegenerative diseases.
To understand axonal pathology in demyelinating disease, it is important to look at myelin and the underlying axon as a closely connected anatomical and functional unit and ask how damage of one component affects survival of the other [20]. Although loss of insulating and metabolic support is one attractive hypothesis to explain how pathology in myelin spreads from glia to the axons, gain-of-toxic function provides an additional explanation. For example, release of toxic lipid species from myelin such as psychosine that is generated during globoid cell leukodystrophy (Krabbe's disease) can spread to the axons where it causes damage [21]. Other neurotoxic lipid species are acylcarnitines, intermediates of fatty acid β-oxidation, which are generated in Schwann cell after mitochondrial dysfunction [22].
In addition, the lipid composition of myelin may change during the course of diseases such as multiple sclerosis or certain leukodystrophies, which may at the end, contribute to myelin destabilization and breakdown.
Here, we will discuss the metabolism of myelin lipids and focus on their role in myelin synthesis, maintenance and diseases.
Section snippets
Cholesterol: the driver
Cholesterol is an essential structural lipid of all mammalian membranes. In the CNS, almost the entire pool of cholesterol is produced in situ from de novo synthesis in a complex 37-step process that is shared between all cell types [23]. However, in contrast to many other cell types, oligodendrocytes do not use glucose but ketone bodies as precursors for the synthesis of cholesterol [24]. Ketone blood concentrations are particularly high in the suckling rat (between 1 and 2 mM; in adult rats,
Galactosylceramides/sulfatides: the stabilizers
Galactosylceramides and sulfatides with long chain fatty acid moieties, in particular 24:0 and 24:1 fatty acids, are the most typical myelin lipids. The rate of accumulation of these lipid species can be used as a measure of myelin biogenesis in the brain.
The biosynthesis of ceramide is followed by the transfer of sugar moieties to generate glucosylceramide and galactosylceramide, which can be further transformed into gangliosides and sulfatides, respectively (Fig. 1).
Mutations in SPTLC1 and
Gangliosides: the communicators
Gangliosides are brain-enriched glycosphingolipids that contain an oligosaccharide head structure with one or more sialic acids (e.g., N-acetyl-neuraminic acid). Ganglioside constitute a large family of lipids with more than 100 different species, of which GM1, GD1a, GD1b and GT1b account for 96% of the gangliosides in the human brain [87]. As the brain develops, there is not only an increase in the amount of gangliosides, but also in their complexity, which is reflected by their degree of
Plasmalogens: the multisided
Another distinguishing feature of myelin lipid composition is the high amount of ethanolamine plasmalogens. Consequently, levels correlate with the degree of myelination and there is an eight-fold increase in ethanolamine plasmalogens levels per gram of brain tissue in the white matter during first year of human life [102]. The highest levels are reached between 30 and 40 years of age when myelination is completed. Plasmalogens contain a vinyl ether linkage at the sn-1 position and an ester
Phosphoinositides: the regulators
The phosphorylation of the inositol headgroup of phosphoinositides at one of three positions gives rise to seven different lipids species [117], [118]. Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), represents with approximately one mole percent of total lipids the most abundant phosphoinositide in the plasma membrane of most cells including myelin [119]. PI(4,5)P2 is primarily formed by type I phosphatidylinositol-4-phosphate-5-kinases from PI(4)P. Alternative but minor routes are the
Conclusion and outlook
We have highlighted structural features and functions of the major myelin lipid species in myelin. Apart from playing a role in regulating specific tasks, lipids also function as collectives. A major function of lipids in myelin is to pack the membrane into a stable, long-lived insulating sheath. A shared phenotype of many mouse mutants, in which lipid generating enzymes have been targeted, is that mutant glia are still able to form myelin. Myelinating glia have a remarkable capacity to
Acknowledgements
The work is supported by grants from the German Research Foundation (SI 746/9-1 and 10-1; TRR43), the GIF, the Tschira-Stiftung, E-Rare program (BMBF). SS received a PhD scholarship from the Boehringer-Ingelheim-Fonds.
References (132)
- et al.
Trends Cell Biol.
(2011) - et al.
J. Lipid Res.
(2011) - et al.
Dev. Cell
(2013) - et al.
J. Lipid Res.
(1965) - et al.
J. Lipid Res.
(1965) - et al.
Biophys. J.
(2011) - et al.
Dev. Cell
(2011) - et al.
Neuron
(2013) - et al.
J. Lipid Res.
(2004) - et al.
Biochim. Biophys. Acta
(1981)
Arch. Biochem. Biophys.
Prog. Lipid Res.
Cell
Biochim. Biophys. Acta
Curr. Opin. Cell Biol.
J. Biol. Chem.
Neuroscience
Cell
J. Biol. Chem.
Cell Rep.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Cell
Biochim. Biophys. Acta
Neuroscience
Nat. Rev. Neurosci.
J. Peripher. Nerv. Syst.
J. Cell Sci.
Annu. Rev. Cell Dev. Biol.
Adv. Neurol.
J. Neurochem.
Curr. Protoc. Cell Biol.
J. Neurochem.
Ann. N. Y. Acad. Sci.
J. Neurochem.
J. Neurosci. Res.
Science
J Cell Biol
J. Neurosci.
Biochem. J.
Biochem. J.
J. Neurochem.
EMBO Rep.
Proc. Natl. Acad. Sci. U. S. A.
Nat. Neurosci.
Science
PLoS Genet.
Proc. Natl. Acad. Sci. U. S. A.
Cited by (169)
Tackling myelin deficits in neurodevelopmental disorders using drug delivery systems
2024, Advanced Drug Delivery ReviewsOligodendrocyte pathology in Huntington's disease: from mechanisms to therapeutics
2023, Trends in Molecular MedicineInfluence of cold-stimulated adipocyte supernatant on the expression of adhesion-related molecules in Schwann cell line
2023, Biochemistry and Biophysics Reports
- ☆
This article is part of a Special Issue titled Brain Lipids.