Review The role of Sphingolipids in myelination and myelin stability and their involvement in childhood and adult demyelinating disorders, 2021, Giussani+

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The role of Sphingolipids in myelination and myelin stability and their involvement in childhood and adult demyelinating disorders
Paola Giussani; Alessandro Prinetti; Cristina Tringali

Multiple sclerosis (MS) represents the most common demyelinating disease affecting the central nervous system (CNS) in adults as well as in children. Furthermore, in children, in addition to acquired diseases such as MS, genetically inherited diseases significantly contribute to the incidence of demyelinating disorders.

Some genetic defects lead to sphingolipid alterations that are able to elicit neurological symptoms. Sphingolipids are essential for brain development, and their aberrant functionality may thus contribute to demyelinating diseases such as MS. In particular, sphingolipidoses caused by deficits of sphingolipid-metabolizing enzymes, are often associated with demyelination.

Sphingolipids are not only structural molecules but also bioactive molecules involved in the regulation of cellular events such as development of the nervous system, myelination and maintenance of myelin stability. Changes in the sphingolipid metabolism deeply affect plasma membrane organization. Thus, changes in myelin sphingolipid composition might crucially contribute to the phenotype of diseases characterized by demyelinalization.

Here, we review key features of several sphingolipids such as ceramide/dihydroceramide, sphingosine/dihydrosphingosine, glucosylceramide and, galactosylceramide which act in myelin formation during rat brain development and in human brain demyelination during the pathogenesis of MS, suggesting that this knowledge could be useful in identifying targets for possible therapies.

Link | PDF (Journal of Neurochemistry)

 

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The CNS is particularly enriched with sphingolipids that are pivotal components of the myelin sheath or of the plasma membranes of resident cells where they modulate processes such as signal transduction, apoptosis, autophagy, senescence, necrosis and differentiation. Ceramide levels are directly interconnected with sphingosine 1-phosphate (S1P) and both these molecules act in signal transduction.

Acid SMase [sphingomyelinase] modulation can favour myelin repair [...] after demyelination induced by cuprizone, in acid SMase-deficient mice models, oligodendrocytes increased, and myelin repair occurred faster than in wild-type controls. [...] Intriguingly, acid SMase deficiency because of genetic defects affecting the SMPD1 gene is the hallmark of Niemann-Pick disease types A (total enzyme deficiency) and B (around 10% residual enzyme activity). Accumulation of SM and cholesterol lead to neuron death which manifests as a severe neurodegeneration in Niemann-Pick type A. In type B, by contrast, neurological involvement is absent or negligible in the majority of subjects.

Sphingolipids are enriched in the CNS and are associated with many biological functions. [...] In particular, specific glycosphingolipids have unique properties essential for their physiological function in forming the tightly packed myelin membrane necessary to isolate neuronal axon. Myelin is abundantly enriched in lipids, particularly cholesterol and sphingolipids. The correct metabolism and supply of these molecules are crucial for the maintenance of physiological functions of the brain and for the development of the nervous system. The altered metabolism of cholesterol and sphingolipids is often associated with neurodegenerative diseases

The myelin sheaths, which are lipid-rich, multilamellar membrane stacks and are produced by oligodendrocytes, are crucial for electric insulation and viability of neurons. The protein and lipid composition of myelin is very peculiar. In fact, the lipid composition of myelin varies significantly from other biological membranes. The sphingolipids are highly abundant and their metabolism is finely tuned; the enzymes involved have different subcellular regulation and, subsequently, the inter-organelle transport can be a point of regulation for metabolic destiny of sphingolipid precursors. It would be very important to understand the regulation of sphingolipid metabolism in myelin formation to treat demyelinating diseases

Sphingolipids are recognized not only as structural molecules but also as regulators of cellular events, for example through the formation of membrane microdomains. Such compartmentalization is involved in pivotal mechanisms such as myelin stability. Increasing evidence implies that microdomains are very heterogeneous, often depending on the sphingolipid variety. Changes in the sphingolipid metabolism can lead to plasma membrane rearrangements that can be responsible for numerous neurological diseases.

mice mutated for different lipid biosynthesis pathways, glial cells involved in myelination have the capacity to overcome the lack of single lipids even if this compensation does not work in maintaining long-term stability of myelin

Recently, it has been demonstrated that S1P in extracellular vesicles produced by microglia, stimulates oligodendrocyte precursor cells migration, that is the first step in myelin repair.

S1P [sphingosine-1-phosphatase] can act as an extracellular as well as an intracellular mediator. Extracellular S1P exerts its effects through specific receptors at the plasma membranes (S1P1-5).

negative role of S1P2 in myelin repair; in fact, S1P2 pharmacological inactivation or gene knockdown is associated with increased myelin repair. Moreover, S1P2 inactivation decreased blood–brain leakage, suggesting a critical role of this S1P receptor in demyelinization through the regulation of blood–brain barrier permeability

during myelination, the impossibility to synthetize specific sphingolipids does not impair the entire process, as missing species are replaced with other lipids belonging to the same family, yet myelin stability is not being kept and thus related symptoms appear early on. [...], in MS, the direct cause of sphingolipid alterations remains obscure.

 

[SNT Gatchaman]

Acid SMase [sphingomyelinase] modulation can favour myelin repair [...] after demyelination induced by cuprizone, in acid SMase-deficient mice models, oligodendrocytes increased, and myelin repair occurred faster than in wild-type controls. [...] Intriguingly, acid SMase deficiency because of genetic defects affecting the SMPD1 gene is the hallmark of Niemann-Pick disease types A (total enzyme deficiency) and B (around 10% residual enzyme activity).

In Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study (2022, PLOS ONE) —

We performed whole exome sequencing using Personalis ACE Clinical Exome sequencing platform to a depth of ~70X and Qiagen QCI-I Translational for data interpretation and variant calling. These results revealed a rare homozygous SMPD1 (sphingomyelin phosphodiesterase 1) variant with uncertain significance (c.808G>A; p. Gly270Ser, CAD score: 23.7, ExAC Frequency: % 0.023, ClinVar Accession: RCV000382375.1) in the extremely severely ill ME/ CFS patient. The observed variant resides in the metallophosphatase (MPP) domain of the SMPD1 gene. Mutations in SMPD1 are associated with sphingomyelin lipidosis, also called sphingomyelinase deficiency or Niemann-Pick disease (NPD) type A/B, a rare lipid storage disorder with autosomal recessive inheritance. NPD type A/B can cause a spectrum of disease with variation in severity and symptomology even among members of the same family. We did not find any rare damaging homozygous SMPD1 variant in the identical twins or unrelated healthy control in their whole exome seq data. These results raise the possibility that the variants in the SMPD1 gene may be responsible for the lipid droplet increase observed in the extremely severe ME/CFS patient.

Note that SSRIs directly downregulate acid sphingomyelinase. See Mechanisms of action of fluvoxamine for COVID-19: a historical review (2022, Nature Molecular Psychiatry) —

SARS-CoV-2 binds to ACE2 receptor on the cells, resulting in acid sphingomyelinase (ASM) activation, converting sphingomyelin to ceramide. The ASM/ceramide system can facilitate viral entry. Antidepressants, such as fluvoxamine, inhibit ASM and ceramide-enriched membrane domain formation, resulting in decreased viral entry.

Note also that activated platelets release S1P. See Activated platelets release sphingosine 1-phosphate and induce hypersensitivity to noxious heat stimuli in vivo (2015, Frontiers in Neuroscience)

 

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See also —

Myelin lipid metabolism and its role in myelination and myelin maintenance (2022, The Innovation)

Abnormal brain diffusivity in participants with persistent neuropsychiatric symptoms after COVID-19 (2023, NeuroImmune Pharmacology and Therapeutics)

MRI with generalized diffusion encoding reveals damaged white matter in patients previously hospitalized for COVID-19 and with persisting symptoms at follow-up (2023, Brain Communications)

(Speculatively: I wouldn't be completely surprised if DecodeME ended up pinging SMPD1 — and perhaps there's more chance given the protocol to more easily include the severely affected.)