Myelin

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Petr75
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Myelin

Post by Petr75 » Wed Jul 29, 2020 7:49 am

2020 Jun 16
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami
Myelin Basic Protein Phospholipid Complexation Likely Competes with Deimination in Experimental Autoimmune Encephalomyelitis Mouse Model
https://pubmed.ncbi.nlm.nih.gov/32637820/


Abstract

Multiple sclerosis has complex pathogenesis encompassing a variety of components (immunologic, genetic, and environmental). The autoimmunogenicity against the host's myelin basic protein is a major contributor. An increase in myelin basic protein deimination (a post-translational modification) and a change in phospholipid composition have been associated with multiple sclerosis. The interaction of myelin basic protein with phospholipids in the myelin membrane is an important contributor to the stability and maintenance of proper myelin sheath function. The study of this aspect of multiple sclerosis is an area that has yet to be fully explored and that the present study seeks to understand. Several biochemical methods, a capillary electrophoresis coupled system and mass spectrometry, were used in this study. These methods identified four specific phospholipids complexing with myelin basic protein. We show that lysophosphatidylcholine 18:1 provides a robust competitive effect against hyper-deimination. Our data suggest that lysophosphatidylcholine 18:1 has a different biochemical behavior when compared to other phospholipids and lysophosphatidylcholines 14:0, 16:0, and 18:0.

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Re: Myelin

Post by NHE » Wed Jul 29, 2020 10:02 pm

Petr75 wrote:
Wed Jul 29, 2020 7:49 am
2020 Jun 16
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami
Myelin Basic Protein Phospholipid Complexation Likely Competes with Deimination in Experimental Autoimmune Encephalomyelitis Mouse Model
https://pubmed.ncbi.nlm.nih.gov/32637820/

...

We show that lysophosphatidylcholine 18:1 provides a robust competitive effect against hyper-deimination. Our data suggest that lysophosphatidylcholine 18:1 has a different biochemical behavior when compared to other phospholipids and lysophosphatidylcholines 14:0, 16:0, and 18:0.
Image

General chemical structure of lysophosphatidylcholines, where R is a variable fatty acid chain.

This is interesting...
Wikipedia wrote:They result from partial hydrolysis of phosphatidylcholines, which removes one of the fatty acid groups. The hydrolysis is generally the result of the enzymatic action of phospholipase A2.[2] Among other properties, they activate endothelial cells during early atherosclerosis[3][4] and stimulate phagocyte recruitment when released by apoptotic cells.[5] Moreover, LPCs can be used in the lab to cause demyelination of brain slices, to mimic the effects of demyelinating diseases such as multiple sclerosis. Further, they are known to stimulate phagocytosis of the myelin sheath and can change the surface properties of erythrocytes.[6] LPC-induced demyelination is thought to occur through the actions of recruited macrophages and microglia which phagocytose nearby myelin. Invading T cells are also thought to mediate this process. Bacteria such as Legionella pneumophila utilize phospholipase A2 end-products (fatty acids and lysophospholipids) to cause host cell (macrophage) apoptosis through cytochrome C release.

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Re: Myelin

Post by NHE » Wed Jul 29, 2020 11:09 pm



Hypothesis model of MBP–phospholipid complexation. (A) Working hypothesis for membrane disruption, incorporating key events associated with unstable myelin. The order of events has yet to be determined. (B) Model of phospholipid (PC 16:1/16:1, PI 18:0/20:4, PS 18:0/18:1, LPC 18:0, LPC 16:0, and LPC 14:0) competitive effects against PAD-mediated hyper-deimination and potential cascade of events. (C) Model of LPC 18:1 competitive effects against PAD-mediated hyper-deimination. Δ, “change in”; MBP, myelin basic protein; and PAD, peptidyl arginine deiminase. Open and C-shaped conformations are consistent with the previously published reports. PC: phosphatidylcholine, PI: phosphatidylinositol, PS: phosphatidylserine, LPC: lysophosphatidylcholine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331039/

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Re: Myelin

Post by Petr75 » Tue Aug 18, 2020 11:02 am

2020 Jul 27
Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
CD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation
https://pubmed.ncbi.nlm.nih.gov/32718316/

Abstract

Background: The presence of foamy macrophages and microglia containing intracellular myelin remnants is a pathological hallmark of neurodegenerative disorders such as multiple sclerosis (MS). Despite the importance of myelin internalization in affecting both central nervous system repair and neuroinflammation, the receptors involved in myelin clearance and their impact on the phagocyte phenotype and lesion progression remain to be clarified.

Methods: Flow cytometry, quantitative PCR, and immunohistochemistry were used to define the mRNA and protein abundance of CD36 in myelin-containing phagocytes. The impact of CD36 and nuclear factor erythroid 2-related factor 2 (NRF2) on the phagocytic and inflammatory features of macrophages and microglia was assessed using a pharmacological CD36 inhibitor (sulfo-N-succinimidyl oleate) and Nrf2-/- bone marrow-derived macrophages. Finally, the experimental autoimmune encephalomyelitis (EAE) model was used to establish the impact of CD36 inhibition on neuroinflammation and myelin phagocytosis in vivo.

Results: Here, we show that the fatty acid translocase CD36 is required for the uptake of myelin debris by macrophages and microglia, and that myelin internalization increased CD36 expression through NRF2. Pharmacological inhibition of CD36 promoted the inflammatory properties of myelin-containing macrophages and microglia in vitro, which was paralleled by a reduced activity of the anti-inflammatory lipid-sensing liver X receptors and peroxisome proliferator-activated receptors. By using the EAE model, we provide evidence that CD36 is essential for myelin debris clearance in vivo. Importantly, CD36 inhibition markedly increased the neuroinflammatory burden and disease severity in the EAE model.

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Re: Myelin

Post by Petr75 » Fri Aug 21, 2020 11:16 am

2020 Jul 26
School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK
Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia
https://pubmed.ncbi.nlm.nih.gov/32722558/

Abstract

The Gas6-TAM (Tyro3, Axl, Mer) ligand-receptor system is believed to promote central nervous system (CNS) (re)myelination and glial cell development. An additional important function of Gas6-TAM signalling appears to be the regulation of immunity and inflammation, which remains to be fully elucidated in the CNS. Here, we characterised the expression of TAM receptors and ligands in individual CNS glial cell types, observing high expression of Gas6 and the TAM receptors, Mer and Axl, in microglia, and high expression of Tyro3 in astrocytes. We also investigated the effect of Gas6 on the inflammatory cytokine response in the optic nerve and in mixed glial cell cultures from wildtype and single TAM receptor knockout mice. In wildtype and Mer-deficient cultures, Gas6 significantly stimulated the expression of the anti-inflammatory/pro-repair cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β), whereas this effect was absent in either Tyro3 or Axl knockout cultures. Furthermore, Gas6 caused upregulation of myelin basic protein (MBP) expression in optic nerves, which was blocked by a neutralising antibody against IL-10. In conclusion, our data show that microglia are both a major source of Gas6 as well as an effector of Gas6 action in the CNS through the upregulation of anti-inflammatory and pro-repair mediators. Furthermore, the presence of both Axl and Tyro3 receptors appears to be necessary for these effects of Gas6. In addition, IL-10, alongside suppressing inflammation and immunity, mediates the pro-myelinating mechanism of Gas6 action in the optic nerve. Therefore, Gas6 may present an attractive target for novel therapeutic interventions for demyelinating as well as neuroinflammatory disorders of the CNS.

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Re: Myelin

Post by Petr75 » Sun Sep 13, 2020 5:53 am

2020 Aug 18
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland
Fractalkine-Dependent Microglial Pruning of Viable Oligodendrocyte Progenitor Cells Regulates Myelination
https://pubmed.ncbi.nlm.nih.gov/32814050/

Abstract

Oligodendrogenesis occurs during early postnatal development, coincident with neurogenesis and synaptogenesis, raising the possibility that microglia-dependent pruning mechanisms that modulate neurons regulate myelin sheath formation. Here we show a population of ameboid microglia migrating from the ventricular zone into the corpus callosum during early postnatal development, termed "the fountain of microglia," phagocytosing viable oligodendrocyte progenitor cells (OPCs) before onset of myelination. Fractalkine receptor-deficient mice exhibit a reduction in microglial engulfment of viable OPCs, increased numbers of oligodendrocytes, and reduced myelin thickness but no change in axon number. These data provide evidence that microglia phagocytose OPCs as a homeostatic mechanism for proper myelination. A hallmark of hypomyelinating developmental disorders such as periventricular leukomalacia and of adult demyelinating diseases such as multiple sclerosis is increased numbers of oligodendrocytes but failure to myelinate, suggesting that microglial pruning of OPCs may be impaired in pathological states and hinder myelination.

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Re: Myelin

Post by Petr75 » Tue Oct 20, 2020 11:24 am

2020 Sep 21
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
Synthesis and Biological Evaluation of Radioiodinated 3-Phenylcoumarin Derivatives Targeting Myelin in Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/32971260/

Abstract

Myelin is a lipid multilayer involved in the rate of nerve transmission, and its loss is a pathological feature of multiple sclerosis in brains. Since in vivo imaging of myelin may be useful for drug development, early diagnosis, and monitoring the disease stage, we designed, synthesized, and evaluated eight novel radioiodinated 3-phenylcoumarin derivatives as imaging probes targeting myelin. In the biodistribution study using normal mice, all compounds displayed sufficient brain uptake, ranging from 2.5 to 5.0% ID/g, at 2 min postinjection. On ex vivo autoradiography, [125I]18 and [125I]21, which have a dimethylamino group, showed high binding affinity for myelin in the normal mouse brain. In addition, the radioactivity accumulation of [125I]21 in the white matter of the spinal cord in the experimental autoimmune encephalomyelitis mice was lower than that in normal mice. These results suggest that [123I]21 shows potential as a single photon emission computed tomography probe targeting myelin.

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Re: Myelin

Post by Petr75 » Thu Oct 22, 2020 2:48 am

2020 Sep 25
University of California, Irvine, United States
N-Acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation
https://pubmed.ncbi.nlm.nih.gov/32978254/

Abstract

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of re-myelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling and endocytosis. N-acetylglucosamine (GlcNAc) is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting PDGF receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, while genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone) induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identifies N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggests oral GlcNAc may be neuro-protective in demyelinating diseases like MS.

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Re: Myelin

Post by Petr75 » Sun Oct 25, 2020 11:17 am

2020 Oct 7
Jülich Centre for Neutron Science at MLZ, Forschungszentrum Jülich GmbH, Garching, Germany
Membrane stiffness and myelin basic protein binding strength as molecular origin of multiple sclerosis
https://pubmed.ncbi.nlm.nih.gov/33028889/


Abstract

Myelin basic protein (MBP) and its interaction with lipids of the myelin sheath plays an important part in the pathology of multiple sclerosis (MS). Previous studies observed that changes in the myelin lipid composition lead to instabilities and enhanced local curvature of MBP-lipid multilayer structures. We investigated the molecular origin of the instability and found that the diseased lipid membrane has a 25% lower bending rigidity, thus destabilizing smooth [Formula: see text]µm curvature radius structures such as in giant unilamellar vesicles. MBP-mediated assembling of lipid bilayers proceeds in two steps, with a slow second step occurring over many days where native lipid membranes assemble into well-defined multilayer structures, whereas diseased lipid membranes form folded assemblies with high local curvature. For both native and diseased lipid mixtures we find that MBP forms dense liquid phases on top of the lipid membranes mediating attractive membrane interactions. Furthermore, we observe MBP to insert into its bilayer leaflet side in case of the diseased lipid mixture, whereas there is no insertion for the native mixture. Insertion increases the local membrane curvature, and could be caused by a decrease of the sphingomyelin content of the diseased lipid mixture. These findings can help to open a pathway to remyelination strategies.

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Re: Myelin

Post by Petr75 » Sat Nov 07, 2020 1:40 pm

2020 Oct 23
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology and Ophthalmology, Harvard Medical School, Boston
Robust Myelination of Regenerated Axons Induced by Combined Manipulations of GPR17 and Microglia
https://pubmed.ncbi.nlm.nih.gov/33108748/

Abstract

Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling myelination after injury and during axon regeneration in the central nervous system (CNS). Previously, we discovered multiple molecular pathways and strategies that could promote robust axon regrowth after optic nerve injury. However, regenerated axons remain unmyelinated, and the underlying mechanisms are elusive. In this study, we found that, in injured optic nerves, oligodendrocyte precursor cells (OPCs) undergo transient proliferation but fail to differentiate into mature myelination-competent oligodendrocytes, reminiscent of what is observed in human progressive multiple sclerosis. Mechanistically, we showed that OPC-intrinsic GPR17 signaling and sustained activation of microglia inhibit different stages of OPC differentiation. Importantly, co-manipulation of GPR17 and microglia led to extensive myelination of regenerated axons. The regulatory mechanisms of stage-dependent OPC differentiation uncovered here suggest a translatable strategy for efficient de novo myelination after CNS injury.

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Re: Myelin

Post by Petr75 » Fri Jan 15, 2021 9:14 am

2021 Jan 11
Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada
An atlas for human brain myelin content throughout the adult life span
https://pubmed.ncbi.nlm.nih.gov/33431990/


Abstract

Myelin water imaging is a quantitative neuroimaging technique that provides the myelin water fraction (MWF), a metric highly specific to myelin content, and the intra-/extra-cellular T2 (IET2), which is related to water and iron content. We coupled high-resolution data from 100 adults with gold-standard methodology to create an optimized anatomical brain template and accompanying MWF and IET2 atlases. We then used the MWF atlas to characterize how myelin content relates to demographic factors. In most brain regions, myelin content followed a quadratic pattern of increase during the third decade of life, plateau at a maximum around the fifth decade, then decrease during later decades. The ranking of mean myelin content between brain regions remained consistent across age groups. These openly available normative atlases can facilitate evaluation of myelin imaging results on an individual basis and elucidate the distribution of myelin content between brain regions and in the context of aging.

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Re: Myelin

Post by Petr75 » Sun Jan 17, 2021 11:20 pm

2020 Jul 28
Department of Medical Biotechnology and Translational Medicine, Università di Milano, Segrate, Italy
The role of Sphingolipids in myelination and myelin stability and their involvement in childhood and adult demyelinating disorders
https://pubmed.ncbi.nlm.nih.gov/33448358/

Abstract

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.

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Re: Myelin

Post by NHE » Mon Jan 18, 2021 1:53 am

Petr75 wrote:
Sun Jan 17, 2021 11:20 pm
2020 Jul 28
Department of Medical Biotechnology and Translational Medicine, Università di Milano, Segrate, Italy
The role of Sphingolipids in myelination and myelin stability and their involvement in childhood and adult demyelinating disorders
https://pubmed.ncbi.nlm.nih.gov/33448358/
Free full text: https://onlinelibrary.wiley.com/doi/epd ... /jnc.15133




Figure 1: Sphingolipid catabolism alterations in demyelinating sphingolipidoses. Sphingolipid catabolic pathways are depicted from complex sphingolipids to sphingosine. Gene alterations associated with metabolic disorders are evidenced by colour squares along with their accumulated substrates. SM: sphingomyelin; Cer: Ceramide; Sph: sphingosine; GalCer: galactosylceramide; GlcCer: glucosylceramide; LacCer: lactosylceramide; Gb3: globotryaosylceramide; Gb4: globoside




Figure 2: Overview of sphingoid and sphingolipid metabolism and correlation with myelin formation and stability.

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Re: Myelin

Post by Petr75 » Tue Jan 19, 2021 7:06 am

Petr75 wrote:
Thu Oct 22, 2020 2:48 am
2020 Sep 25
University of California, Irvine, United States
N-Acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation
https://pubmed.ncbi.nlm.nih.gov/32978254/

Abstract

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of re-myelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling and endocytosis. N-acetylglucosamine (GlcNAc) is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting PDGF receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, while genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone) induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identifies N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggests oral GlcNAc may be neuro-protective in demyelinating diseases like MS.
2020 Dec 18
Department of Neurology, University of California Irvine, Irvine, California, USA
N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation
https://pubmed.ncbi.nlm.nih.gov/33453988/

Abstract

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.

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