Myelin lipid metabolism and its role in myelination and myelin maintenance, 2022, Barnes-Vélez et al

[SNT Gatchaman]

Myelin lipid metabolism and its role in myelination and myelin maintenance
Barnes-Vélez JA, Aksoy Yasar FB, Hu J

Myelin is a specialized cell membrane indispensable for rapid nerve conduction. The high abundance of membrane lipids is one of myelin's salient features that contribute to its unique role as an insulator that electrically isolates nerve fibers across their myelinated surface. The most abundant lipids in myelin include cholesterol, glycosphingolipids, and plasmalogens, each playing critical roles in myelin development as well as function.

This review serves to summarize the role of lipid metabolism in myelination and myelin maintenance, as well as the molecular determinants of myelin lipid homeostasis, with an emphasis on findings from genetic models. In addition, the implications of myelin lipid dysmetabolism in human diseases are highlighted in the context of hereditary leukodystrophies and neuropathies as well as acquired disorders such as Alzheimer's disease.

PubMed | Link | PDF

 

[SNT Gatchaman]

Open access. I'll summarise and highlight the text, with links.

CGT - cerebroside galactosyl-transferase
CNS - central nervous system
ER - endoplasmic reticulum
GalC - galactocerebride (aka galactosylceramide)
GSL - glycosphingolipid
mTOR - mammalian target of rapamycin
mTORC - mammalian target of rapamycin complex (1 and 2)
OL - oligodendrocyte (CNS)
OPC - oligodendrocyte precursor cell
PE - phosphatidylethanolamine
PNS - peripheral nervous system
PPAR - peroxisome proliferator-activated receptor
QKI - quaking (homologue)
SC - Schwann cell (PNS)
SREBP - sterol regulatory element-binding protein

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Myelin is a lipid-rich, multilamellar membrane that insulates axons and enables an ion channel configuration necessary for saltatory action potentials that markedly enhance nerve conduction velocity. In the central nervous system (CNS), myelin primarily forms postnatally and is produced by multiprocessed, neuroepithelium-derived oligodendrocytes (OLs). OL numbers peak in early life and are highly stable during the human lifespan, yet new OLs continually arise and initiate adaptive myelination throughout adulthood.

In the peripheral nervous system (PNS), large-caliber (>1 mm) axons are myelinated by neural crest-derived Schwann cells (SCs), whereas small-caliber axons are enwrapped by non-myelinated SCs. [...] Similar to OLs, SC-mediated myelination occurs postnatally; moreover, once established, SC numbers are stable with minimal cell turnover.

Among the biochemical properties unique to myelin compared with other cell membranes is the relatively high ratio of lipids to proteins, as more than 70% of myelin consists of lipids. In contrast to myelin proteins, many of which are myelin specific, myelin lipid species are non-specific; however, the myelin lipid composition is distinctive, with a characteristic overrepresentation of cholesterol, galactocerebrosides (GalC), sulfatides, and plasmalogens.

Yet various questions involving myelin lipids remain unaddressed, particularly regarding the contribution of lipid metabolism to myelin maintenance, as well as the underlying molecular determinants of myelin lipid homeostasis.

 

[SNT Gatchaman]

Cholesterol is highly enriched in myelin compared with other cell membranes and is the most abundant lipid in both the CNS and the PNS. Cholesterol resides within the phospholipid bilayer, where it stabilizes membrane proteins and helps establish the fluidity and permeability of plasma membranes. Importantly, cholesterol synthesis and trafficking in myelinating glia have critical functions in myelin development and homeostasis.

Studies targeting lipid transporters further illuminated the impact of lipid influx on myelination and myelin repair. In adult mice with inducible whole-body depletion of low-density lipoprotein receptor-related protein 1 (LRP1), a cholesterol importer, remyelination was significantly impaired after toxin-induced demyelination. Inducible and conditional knockout of Lrp1 in OL precursor cells (OPCs) replicated the remyelination deficits; moreover, depletion of Lrp1 across the OL lineage led to hypomyelination, indicating that cholesterol uptake specifically by OLs is important to myelin development and repair.

Complementary approaches reinforcing cholesterol’s role in myelination have included pharmaceutical and genetic targeting of upstream regulators of cholesterol synthesis. For instance, challenging adult mice with simvastatin, a cholesterol-lowering drug that inhibits sterol synthesis, induced demyelination, reduced mature OL numbers, and decreased OPC differentiation.

In summary, myelin is highly dependent on both astrocyte- and OL-derived cholesterol in the CNS; however, whether other astrocyte-derived lipids contribute to myelination and myelin maintenance remains elusive.

 

[SNT Gatchaman]

Glycosphingolipids (GSLs) are a major glycolipid subtype that includes GalC and their sulfated form, sulfatides. [...] consist of a fatty acid attached to a sphingosine backbone and are synthesized in the ER.

GalC and sulfatides are abundantly present in myelin and enhance myelin compaction stability through trans interactions between apposing lipid bi-layers. [...] indispensable for normal myelin structure and long-term myelin stability.

... myelination follows unimpaired, albeit defectively, in mice lacking the GalC-synthesizing enzyme cerebroside galactosyl-transferase (CGT), loss of which blocks GalC and sulfatide production. However, by 2 months of age, myelin vacuolization and demyelination occurred in mutants. Nerve conductivity in CGT-null mice diminished due to paranodal defects, accompanied by tremors and ataxia. Interestingly, targeted loss of sulfatides through knockout of ceramide sulfotransferase (CST), which impaired sulfatide synthesis while leaving GalC levels intact, evinced a milder phenotype relative to mutants lacking both GalC and sulfatides, possibly indicating a greater role for GalC in myelin sheath compactness and stability.

In addition, myelin in CST-null mice demonstrated vacuolar degeneration and aberrant paranodal loops that were aggravated with age. These findings, in line with previous myelin ultrastructural analyses, suggest that sulfatides are necessary for maintaining paranodal junctions

Paranodal loops - see Node of Ranvier: "The internodal glial membranes are fused to form compact myelin, whereas the cytoplasm-filled paranodal loops of myelinating cells are spirally wrapped around the axon at both sides of the nodes. This organization demands a tight developmental control and the formation of a variety of specialized zones of contact between different areas of the myelinating cell membrane."

 

[SNT Gatchaman]

Most phospholipids are formed through the esterification of fatty acids to a glycerol backbone, forming a diacylglycerol lipid moiety with an attached polar head group. However, an estimated 10%–20% of phospholipids possess only one ester-linked acyl chain together with an ether-linked alkyl chain forming ether phospholipids. Ether phospholipids with a vinyl bond are classified as plasmenyl phospholipids or, more commonly, as plasmalogens and constitute the vast majority of ether phospholipids.

Plasmalogens are partially synthesized in peroxisomes and are particularly abundant in myelin. [...] Plasmalogens exist primarily as phosphatidylethanolamine (PE) phospholipids.

In myelin, more than 80% of PE lipids are constituted by plasmalogens, making them a significant contributor to myelin lipid composition.

Other roles attributed to plasmalogens include serving as a reservoir for arachidonic acid, modulating intracellular radical oxygen species propagation, regulating cell death, and contributing to lipid raft formation.

Plasmalogen deficiency through knockout of peroxisome-related genes, such as Pex7 and Gnpat, is detrimental to myelination and myelin stability.

 

[SNT Gatchaman]

Fatty acids are the essential building blocks for the various major myelin lipid species detailed above, and loss of fatty acid metabolism-related gene products has further elucidated the importance of lipid metabolism in myelin homeostasis.

Lipidomic profiles of the peripheral nerves revealed depletion of myelin complex lipids such as ce- ramides and cerebrosides.86 Of interest, dietary supplementation did not ameliorate the mutant phenotype, suggesting that de novo fatty acid synthesis by SCs is indispensable.

... peroxisome proliferator-activated receptor gamma (PPARɣ)-dependent activity contributed to fatty acid synthesis in SCs, as treatment with PPARɣ agonists partially rescued PNS hypomyelination. [...] findings were later recapitulated in the CNS

The mechanisms for these contrasting outcomes between the CNS and the PNS remain undefined but are possibly related to differences in exogenous lipid use between SCs and OLs or through contributions of dietary lipids mediated by other cell types not shared between the CNS and the PNS, such as astrocytes.

 

[SNT Gatchaman]

Myelin lipid metabolism is tightly regulated by various molecular determinants, the most prominent of which include SREBPs, mammalian target of rapamycin (mTOR) complexes, PPARs, and quaking (QKI).

The PPARs comprise a family of three closely related ligand-activated transcription factors, namely PPAR⍺, PPARβ, and PPARɣ. Lipids, including eicosanoids and phospholipids, serve as endogenous ligands for PPARs.

PPARs regulate multiple pathways that contribute to various biological processes, including mitochondrial homeostasis, adipogenesis, and inflammation.
Within the PPAR family, PPARβ has been particularly associated with myelination and myelin homeostasis. PPARβ is abundantly expressed in the brain, with differential expression in neurons and OLs.

an abnormal lipid profile in SCs secondary to loss of SREBP1c leads to dysregulated PPAR⍺ activation, elevated fatty acid oxidation, and aberrant hypermyelination, highlighting the need for a balance between lipogenic and oxidative processes in myelin-forming glia, in which distinctive PPARs may have opposing roles.

Once in the nucleus, SREBPs activate transcription of cholesterol and fatty acid biosynthesis genes that are critical for myelination. [...] SREBP2 is regarded as the primary regulator for cholesterol metabolism. During cellular lipid homeostasis, both family members can act as lipid sensors, providing feedback for intracellular cholesterol levels in order to fine-tune expression of lipid biosynthesis genes in response to lipid supply and demand

 

[SNT Gatchaman]

mTOR is a serine/threonine protein kinase that controls cellular metabolism and growth. mTOR constitutes the catalytic kinase domain for two distinct complexes, mTORC1 and mTORC2.

mTORC2 influences cellular proliferation and survival. Of note, mTORC1 has been shown to activate the lipid master regulators SREBP1a, SREBP1c, and SREBP2, leading to increased transcription of fatty acid and cholesterol biosynthesis genes.

The proposed mechanisms of mTORC1-mediated activation of SREBPs include modulating the availability of cholesterol in the ER by regulating autophagic and lysosomal pathways

Unlike the PNS, CNS myelination is regulated by both mTORC1 and mTORC2. [...] These observations suggest that both mTORC complexes critically contribute to myelin maintenance in the spinal cord.

Interestingly, mTOR activity requires tight control during myelination, as both suppression and hyperactivation disturb myelin homeostasis.

 

[SNT Gatchaman]

... lipids play diverse roles in myelin homeostasis and are regulated by various key molecular determinants. However, one aspect less appreciated but no less vital is the role of lipid metabolism in supporting myelin maintenance specifically, which merits special focus given the growing attention to myelin maintenance and plasticity in adults

Although myelin has been traditionally regarded as highly stable and metabolically inert, its maintenance is now more appreciated as a dynamic and active process, wherein myelin membrane turnover represents a significant component.

the majority of OLs are formed within the first 5 years of life, with an annual turnover of 0.32% in adult life.

In the PNS, SC stability in the sciatic nerve is even more robust than that of OLs, since in vivo proliferation assays revealed minimal turnover in myelinating SCs and an estimated turnover rate of more than 70 months for non-myelinating SCs. In contrast to the slow turnover of myelinating glia, myelin membrane undergoes a more frequent renewal, with 14C measurements in humans indicating a continual turnover of myelin on a yearly basis. Interrogation of myelin-specific proteins and lipids has revealed that continual synthesis is required for myelin maintenance, albeit at significantly varied degrees.

In contrast to proteins, myelin lipids experience faster exchange rates, and myelin maintenance is more vulnerable to lipid dysmetabolism.

... although cholesterol has a fairly stable half-life, phospholipids experience more rapid turnover, with a half-life approaching 3 weeks. In addition to lipid tracing, investigation of QKI demonstrated a critical link between lipid turnover and myelin maintenance for the first time through genetic approaches.

impaired oxidative phosphorylation secondary to COX10 deficiency in SC induced significant neuropathy and PNS dysmyelination similar to Tfam knockout; however, here insufficient energy production was the ascribed mechanism.

 

[SNT Gatchaman]

Hypomyelinating and demyelinating disorders known as leukodystrophies provide a genetic link between lipid metabolism and myelin maintenance, as their underlying mutations commonly occur in genes directly involved in lipid metabolic pathways.

... mutations affecting fatty acid oxidation in peroxisomes can lead to leukodystrophy. Loss of function of ATP-binding cassette subfamily D member 1 (ABCD1) causes X-linked adrenoleukodystrophy (ALD).

Of interest, separate gain-of-function mutations in FAR1 that aberrantly increase plasmalogens also correlate with disrupted neurodevelopment, suggesting that neurological and, likely, myelin homeostasis rest on delicately balanced plasmalogen levels.

Additional lipid and fatty acid metabolic pathways can affect myelin homeostasis and development.

Altogether, this non-exhaustive enumeration of various leukodystrophies supports an interdependence between myelin formation and stability and lipid homeostasis.

 

[SNT Gatchaman]

Brain lipids, including those enriched in myelin, decrease with age. Moreover, with aging there is a concomitant decline in myelin stability. [...] Two observations related to myelin are noteworthy in [Alzheimer Disease]. First, AD is accompanied by significant perturbations in brain lipid metabolism, particularly for lipids abundant in myelin. Second, myelin instability contributes to AD progression.

MRI studies of healthy controls and AD patients demonstrated accelerated decline in white matter integrity in AD patients versus age-matched controls. In addition, imaging studies revealed white matter perturbations in presymptomatic familial AD cases and intracortical demyelination in preclinical AD.

 

[SNT Gatchaman]

Concluding —

Myelin requires enrichment of diverse lipids, including cholesterol, GalC, and plasmalogens. Disruption of lipid metabolism is detrimental to myelin formation and stability, an observation reinforced by mouse and human genetic studies.

Various mutations associated with demyelination suggest that myelin health requires intact lipid pathways with a steady equilibrium between lipid synthesis and degradation.

... various questions remain unaddressed. For instance, the functions of diverse lipid classes in myelin maintenance remain poorly understood. In addition, the source of these lipids is not always clear. Myelin-producing glia have naturally been the focus of this question, but this could leave underappreciated the contributions of supporting cells and circulating lipids.

 

[SNT Gatchaman]

So my questions would be: if lipid metabolism is systemically deranged, could that be causing impairments to myelin structure? Those impairments would not be at the level seen in eg MS or the genetically-determined leukodystropies; instead they could produce much more subtle changes to myelin and nodal structure and composition.

I would expect these sorts of effects could very well cause time- and spatial-varying symptoms due to non-deterministic effects on conduction velocities or interaxonal cross-talk. As outlined above, myelin is dynamic and dependent on lipid metabolism with some components having turnover of weeks. That could also cause non-fixed neurological deficits, that might defy a simplistic neurological model (see FND, functional motor, sensory and seizure disorders).

 

[Hoopoe]

Plasmalogens were decreased in ME/CFS. Low plasmalogens are associated with neurodegeneration and cognitive impairment.

 

[Andy]

Other "myelin" threads.

Evidence for aerobic ATP synthesis in isolated myelin vesicles, 2009, Ravera et al
Myelin sheath: A new possible role in sleep mechanism, 2011, Morelli et al
Myelin sheath and cyanobacterial thylakoids as concentric multilamellar structures with similar bioenergetic properties, 2021, Morelli et al
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation, 2021, Fernandez, Monje, Nath et al

 

[Andy]

A non-member has suggested that this article by Morelli that talks about energy production in the myelin sheath might be of interest, https://researchfeatures.com/wp-content/uploads/2022/07/Alessandro-Maria-Morelli.pdf

as well as this paper, Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice, 2022, Gargareta et al

 

[Creekside]

Did you come across any mention of the effects of circulating fatty acids? I've become intolerant of fibre metabolites, possibly propionate, and I can certainly imagine that the local availability of fatty acids could affect how the membranes (or mylelin) is assembled. Maybe, for example, a certain ion transport pore is formed when x molecules of propionate are collected at a point on the forming membrane.

 

[SNT Gatchaman]

A non-member has suggested that this article by Morelli that talks about energy production in the myelin sheath might be of interest

"I would like to investigate the mechanism of action of general anesthetics, a mechanism that still remains unknown today, despite being very effective, enabling the extraordinary advances that we all know of surgery. Preliminary data indicates that general anesthetics end up in myelin. Since it is known that they are decouplers of oxidative phosphorylation, they would prevent ATP production by myelin with consequent blocking of nerve conduction no longer supported by ATP. The similarities are remarkable between the state of unconsciousness due to the effect of general anesthetics and sleep. In effect, general anesthetics block the gap junctions and therefore block sending ATP to the axon by myelin, just as would happen during sleep. On the other hand, the sympathetic nervous system that controls the function of vital organs (such as the heart and lung) is not myelinated and therefore does not respond to the action of general anesthetics. Indeed, if anesthetics also acted on this nervous system it would be lethal. It is clear that knowledge of the mechanism of action of general anesthetics would pave the way for their improvement."

 

[SNT Gatchaman]

Not sure about the idea referenced in the poster from #16 of "preventing ATP production by myelin", but the idea that the lipid structure in myelin can become deranged could be a good explanation for the observation of apparent disease onset following major surgery (typically framed as due to "stress"). GAs have been used safely in millions for decades, but I can imagine a situation of regionally impaired myelin microstructure that is compensated, so subclinical in terms of recognised symptoms, but the subsequent metabolic insult tips beyond compensation/homeostasis.

Also as a summary, the reference to the sympathetic nervous system being unmyelinated doesn't seem quite right. As far as I know the ANS is myelinated centrally, but many of the post-ganglionic fibres aren't. BP control under anaesthesia is important and multi-factorial and I'm sure the ANS would be a large part of that. (Mechanical ventilation is already required due to muscle relaxants paralysing the respiratory muscles.)