Myelin-associated Glycoprotein Research Articles

Primary neurolymphomatosis with MAG antibody: a case report

Neurolymphomatosis (NL) is a rare neurologic manifestation of non-Hodgkin lymphoma (NHL) with poor prognosis. Investigations including MRI, PET/CT, nerve biopsy and cerebrospinal fluid (CSF) analysis can aid the diagnosis of NL. In this study, we presented a case of NL with co-existing myelin-associated glycoprotein (MAG) antibody. The patient first presented with symptoms of peripheral neuropathy involving multiple cranial nerves and cauda equina, and later developed obstructive hydrocephalus and deep matter lesions. He also had persistently positive MAG antibody, but did not develop electrophysiologically proven neuropathy and monoclonal immunoglobulin. The final brain biopsy confirmed diffuse large B cell lymphoma.

Myelination by signaling through Arf guanine nucleotide exchange factor.

During myelination, large quantities of proteins are synthesized and transported from the endoplasmic reticulum (ER)-trans-Golgi network (TGN) to their appropriate locations within the intracellular region and/or plasma membrane. It is widely believed that oligodendrocytes uptake neuronal signals from neurons to regulate the endocytosis- and exocytosis-mediated intracellular trafficking of major myelin proteins such as myelin-associated glycoprotein (MAG) and proteolipid protein 1 (PLP1). The small GTPases of the adenosine diphosphate (ADP) ribosylation factor (Arf) family constitute a large group of signal transduction molecules that act as regulators for intracellular signaling, vesicle sorting, or membrane trafficking in cells. Studies on mice deficient in Schwann cell-specific Arfs-related genes have revealed abnormal myelination formation in peripheral nerves, indicating that Arfs-mediated signaling transduction is required for myelination in Schwann cells. However, the complex roles in these events remain poorly understood. This review aims to provide an update on signal transduction, focusing on Arf and its activator ArfGEF (guanine nucleotide exchange factor for Arf) in oligodendrocytes and Schwann cells. Future studies are expected to provide important information regarding the cellular and physiological processes underlying the myelination of oligodendrocytes and Schwann cells and their function in modulating neural activity.

Identification of brain-enriched proteins in CSF as biomarkers of relapsing remitting multiple sclerosis

BackgroundMultiple sclerosis (MS) is a clinically and biologically heterogenous disease with currently unpredictable progression and relapse. After the development and success of neurofilament as a cerebrospinal fluid (CSF) biomarker, there is reinvigorated interest in identifying other markers of or contributors to disease. The objective of this study is to probe the predictive potential of a panel of brain-enriched proteins on MS disease progression and subtype.MethodsThis study includes 40 individuals with MS and 14 headache controls. The MS cohort consists of 20 relapsing remitting (RR) and 20 primary progressive (PP) patients. The CSF of all individuals was analyzed for 63 brain enriched proteins using a method of liquid-chromatography tandem mass spectrometry. Wilcoxon rank sum test, Kruskal-Wallis one-way ANOVA, logistic regression, and Pearson correlation were used to refine the list of candidates by comparing relative protein concentrations as well as relation to known imaging and molecular biomarkers.ResultsWe report 30 proteins with some relevance to disease, clinical subtype, or severity. Strikingly, we observed widespread protein depletion in the disease CSF as compared to control. We identified numerous markers of relapsing disease, including KLK6 (kallikrein 6, OR = 0.367, p < 0.05), which may be driven by active disease as defined by MRI enhancing lesions. Other oligodendrocyte-enriched proteins also appeared at reduced levels in relapsing disease, namely CNDP1 (carnosine dipeptidase 1), LINGO1 (leucine rich repeat and Immunoglobin-like domain-containing protein 1), MAG (myelin associated glycoprotein), and MOG (myelin oligodendrocyte glycoprotein). Finally, we identified three proteins—CNDP1, APLP1 (amyloid beta precursor like protein 1), and OLFM1 (olfactomedin 1)—that were statistically different in relapsing vs. progressive disease raising the potential for use as an early biomarker to discriminate clinical subtype.ConclusionsWe illustrate the utility of targeted mass spectrometry in generating potential targets for future biomarker studies and highlight reductions in brain-enriched proteins as markers of the relapsing remitting disease stage.

Paraproteinemic neuropathies.

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.

Exploring Dimethylsulfoniopropionate as a potential treatment for Alzheimer's disease: A study using the 3 × Tg-AD mouse model

BackgroundAlzheimer's disease (AD), the most common neurodegenerative disorder, affects a broad spectrum of aging populations. AD is characterized by pathological amyloid-β (Aβ) plaques and neurofibrillary tangles, leading to neural degeneration and cognitive decline. The lack of effective treatments for AD highlights the urgent need for novel therapeutic agents, particularly in the early stages. Dimethylsulfoniopropionate (DMSP) is a natural marine compound with antioxidant and neuroprotective properties. However, studies on the efficacy of DMSP in the treatment of AD and its associated mechanisms are limited. PurposeThis study aimed to explore the therapeutic effects and mechanisms of action of DMSP as an AD treatment using a preclinical 3 × Tg-AD mouse model. MethodsThe research involved administering DMSP (7 μg/mL and 11 μg/mL in drinking water) to four-month-old 3 × Tg-AD mice consecutively for three months. The Y-maze test, novel object recognition test, and Morris water maze test were used to assess memory and learning ability. The relative expression levels and distribution of proteins relevant to Aβ and tau pathology, synapses, and glial cells were analyzed using western blotting and immunofluorescence assays. Additionally, proteomic and bioinformatics approaches were used to explore the potential targets of DMSP treatment. ResultsDMSP-treated AD mice showed significantly enhanced cognitive function, suggesting that DMSP mitigates memory and learning impairments in AD. Moreover, DMSP diminished the abnormal accumulation of Aβ and phosphorylated tau in both the cortex and hippocampus, which are crucial hallmarks of AD pathology. In addition to its neuroprotective properties, DMSP restored synaptic density and the expression of synaptic and neuronal proteins, which are essential for proper brain function. DMSP displayed anti-inflammatory properties, as evidenced by its ability to suppress inflammatory astrocytes and maintain microglial homeostasis. Notably, DMSP facilitated the maturation of oligodendrocytes (OLs) from oligodendrocyte progenitor cells (OPCs), a critical process in the development of the brain myelination architecture. Proteomic analysis revealed that DMSP positively influenced biological processes crucial for oligodendrocyte development, myelination, and axonal ensheathment, which are often compromised in patients with AD. Protein validation and brain tissue staining supported the role of DMSP in preserving myelin enrichment and sheath integrity. These therapeutic effects were largely attributed to the enhanced expression of myelin-associated glycoprotein (Mag) and tetraspanin Cd9. ConclusionOverall, our findings highlight DMSP as a promising novel therapeutic candidate for AD, offering multifaceted benefits in cognitive and memory enhancement, reduction of Aβ and tau pathology, neuronal synapse protection, anti-inflammatory effects, and myelin sheath restoration as an innovative target compared to other studies. In addition to being a potentially effective treatment for AD, DMSP may also have the potential to address other neurodegenerative diseases that are closely associated with myelin impairment.

The Effects and Mechanism of Scutellaria baicalensis Georgi Stems and Leaves Flavonoids on Myelin Sheath Degeneration Induced by Composite Aβ in Rats.

Alzheimer's disease is a degenerative disease of the central nervous system, and its characteristic pathological changes are closely associated with Aβ deposition and neurofibrillary tangles. Many studies have found that malignant changes in the myelin sheath and oligodendrocyte (OL) are accompanied by the occurrence and development of AD. Therefore, any method that can resist myelin sheath and OL disorders may be a potential strategy for AD. To investigate the effects and mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on the myelin sheath degeneration induced by Aβ25-35 combined with AlC13 and RHTGF-β1 (composite Aβ) in rats. A rat AD model was established by intracerebroventricular injection of composite Aβ. The Morris water maze was used to screen the memory impairment rat model. The successful model rats were divided into the model group and the 35, 70, and 140 mg/kg SSFS groups. The myelin sheath changes in the cerebral cortex were observed with an electron microscope. The expression of the oligodendrocyte- specific protein claudin 11 was detected with immunohistochemistry. The protein expression levels of myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG) and myelin basic protein (MBP), sphingomyelin synthase-1 (SMS1), and sphingomyelinase-2 (SMPD2) were assayed by Western blotting. The intracerebroventricular injection of composite Aβ caused degeneration of the myelin sheath structure and was accompanied by the decreased claudin 11, MOG, MAG, MBP, and SMS1, and increased SMPD2 protein expression in the cerebral cortex. However, 35, 70, and 140 mg/kg SSFs can differentially ameliorate the above abnormal changes induced by composite Aβ. SSFs can alleviate myelin sheath degeneration and increase the protein expression of claudin 11, MOG, MAG, and MBP, and the effective mechanism may be related to the positive regulation of SMS1 and SMPD2 activities.

Abstract 6594: 4-1BB: A double-edged sword for T cells

Abstract Background: The costimulatory receptor 4-1BB (CD137) is expressed on the surface of activated T cells, playing a pivotal role in enhancing T cell responses and emerging as a promising target for cancer immunotherapy. Its primary ligand, 4-1BBL (CD137L), is found on antigen-presenting cells and various immune cells. The interaction between 4-1BBL and 4-1BB provides crucial costimulatory signals to both CD4+ and CD8+ T cells, amplifying their activation and effector functions. However, recent studies have shed light on a distinct role of 4-1BB in T cells. Prior work has revealed that 4-1BB can distinguish intratumoral regulatory T cells (Tregs) from peripheral Tregs and other CD4 lineage T cells in cancer patients, and the overexpression of 4-1BB on Tregs has been associated with unfavorable survival outcomes. Additionally, targeting 4-1BB with IgG2a isotype antibodies has shown significant anti-tumor efficacy in preclinical models by depleting Tregs. Furthermore, agonist monoclonal antibodies targeting 4-1BB have not only shown promise in inducing tumor regressions but also demonstrated improved outcomes in mouse models of autoimmune diseases induced by autoreactive CD4+ T cells. These findings indicate the existence of specific ligands or factors that modulate 4-1BB function on T cells that can vary depending on the disease state. Methods: To identify potential ligand(s) involved in the modulation of 4-1BB function, we developed an innovative CRISPR/Cas9-based transcriptional activation (CRISPRa) screening system that integrates CRISPR/Cas9-guide mediated gene activation, high avidity bead-based selection, serial enrichment, and flow cytometry-based monitoring. This screening platform provides enhanced sensitivity for identifying extracellular interactions between receptor-ligand partners that have not been fully characterized before, even with low-affinity. Results: Through our unbiased CRISPRa screen, we discovered that Myelin-Associated Glycoprotein (MAG), also known as siglec-4, a member of the siglec (sialic acid-binding immunoglobulin-like lectins) family, interacts with 4-1BB in trans. Our study demonstrated that MAG binds to activated T cells via 4-1BB and inhibits their activation and proliferation, suggesting a potential role of the MAG-4-1BB interaction in modulating T cell function. Notably, our data revealed that trans-binding to MAG-positive cells inhibits c-Jun signaling in activated T cells. Furthermore, the presence of MAG on target cells can hinder Chimeric Antigen Receptor (CAR) T-cell activity. Conclusion: Utilizing a highly efficient cell-based CRISPRa system, we discovered a novel interactor of 4-1BB capable of modulating T cell activation through its interaction with 4-1BB. This interaction suggests an immunosuppressive role of 4-1BB, explaining the paradoxical roles of 4-1BB in T cells. These findings provide crucial insights for the development of precise therapeutics targeting 4-1BB. Citation Format: Liping Yang, Timothy P. Sheets, Yang Feng, Kuo-Sheng Hsu, Guojun Yu, Steven Seaman, Pradip Bajgain, Daeho So, Jaewon Lee, Raj Chari, Brad St. Croix. 4-1BB: A double-edged sword for T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6594.

Single cell transcriptome analysis of the THY-Tau22 mouse model of Alzheimer’s disease reveals sex-dependent dysregulations

Alzheimer’s disease (AD) progression and pathology show pronounced sex differences, but the factors driving these remain poorly understood. To gain insights into early AD-associated molecular changes and their sex dependency for tau pathology in the cortex, we performed single-cell RNA-seq in the THY-Tau22 AD mouse model. By examining cell type-specific and cell type-agnostic AD-related gene activity changes and their sex-dimorphism for individual genes, pathways and cellular sub-networks, we identified both statistically significant alterations and interpreted the upstream mechanisms controlling them. Our results confirm several significant sex-dependent alterations in gene activity in the THY-Tau22 model mice compared to controls, with more pronounced alterations in females. Both changes shared across multiple cell types and cell type-specific changes were observed. The differential genes showed significant over-representation of known AD-relevant processes, such as pathways associated with neuronal differentiation, programmed cell death and inflammatory responses. Regulatory network analysis of these genes revealed upstream regulators that modulate many of the downstream targets with sex-dependent changes. Most key regulators have been previously implicated in AD, such as Egr1, Klf4, Chchd2, complement system genes, and myelin-associated glycoproteins. Comparing with similar data from the Tg2576 AD mouse model and human AD patients, we identified multiple genes with consistent, cell type-specific and sex-dependent alterations across all three datasets. These shared changes were particularly evident in the expression of myelin-associated genes such as Mbp and Plp1 in oligodendrocytes. In summary, we observed significant cell type-specific transcriptomic changes in the THY-Tau22 mouse model, with a strong over-representation of known AD-associated genes and processes. These include both sex-neutral and sex-specific patterns, characterized by consistent shifts in upstream master regulators and downstream target genes. Collectively, these findings provide insights into mechanisms influencing sex-specific susceptibility to AD and reveal key regulatory proteins that could be targeted for developing treatments addressing sex-dependent AD pathology.

Kinetics of brain gangliosides binding to myelin-associated glycoprotein from fluctuation analysis of single liposome binding events

Kinetics of brain gangliosides binding to myelin-associated glycoprotein from fluctuation analysis of single liposome binding events

Abstract WP320: Microemboli Model of Vascular Cognitive Impairment/Dementia (VCID) Presents With Long-Term Brain Tissue Hypoxia: Relevance to Endothelin-1 (ET-1)

Diabetes doubles the risk of VCID but the underlying reasons remain unclear. Given that diabetes mediates early endothelial dysfunction and activates the ET system, post-mortem brain ET-1 levels correlate with tissue hypoxia and disease severity in patients with dementia, and microemboli (ME) are more common in diabetic individuals, the goals of the current study were to investigate 1) the relationship between the brain ET system, hypoxia and neuroinflammation in a clinically relevant model of VCID, and 2) the impact of improving endothelial function on the ET system. At 10 weeks after the onset of diabetes, control and diabetic rats received cholesterol crystal ME (40-70 μm) injections and were monitored for 16 weeks. Another cohort received isosorbide mononitrate (ISMN, 75 mg/kg/day) and cilostazol (CZL, 60 mg/kg/day). Behavioral tests included novel object recognition (NOR) and Y-maze. After termination, brain tissue levels of ET-1/ETA/ETB, hypoxia markers myelin-associated glycoprotein (MAG), proteolipid protein-1 (PLP-1) and hypoxia-inducible factor-1α (HIF-1α), and microglia activation were analyzed by ELISA and immunoblotting. Diabetic animals had baseline deficits in certain cognitive domains that progressively worsened and treatment with (ISMN/CZL) prevented decline in cognitive function. HIF-1α levels were higher and MAG levels were lower in the ME cohorts indicating tissue hypoxia. MAG/PLP-1 ratio was even lower in diabetic ME animals (Table 1). ISMN/CZL treatment reduced HIF1α levels in the brain. While there was no dramatic change in plasma and brain tissue ET-1 levels, brain ET-1 levels correlated with HIF-1α (r 2 =0.53, p=0.0073) and MAG/PLP (r 2 =0.45, p=0.0167) in this model of VCID. The causal relationship between ET-1 and brain hypoxia, as well as neuroinflammation, needs further investigation. Strategies to improve vascular function by modulation of the ET system blockade can be a preventive and therapeutic strategy for VCID.

Plasma Lipidomics Profiling to Identify the Biomarkers of Diagnosis and Radiotherapy Response for Advanced Non-Small-Cell Lung Cancer Patients.

Advanced lung cancer that contributes to a heavy burden on medical institutions is the leading cause of cancer-related death and is often accompanied by metabolic disorders. In this study, we aimed to explore the biomarkers of diagnosis and radiotherapy response in non-small-cell lung cancer (NSCLC) patients by plasma lipidomics analysis. Using triple-quadrupole mass spectrometer analysis, our research characterized the plasma lipid metabolomics profile of 25 healthy controls and 31 advanced NSCLC patients in each of three different radiotherapy phases. The results showed altered lipid elements and concentrations among NSCLC patients with different radiotherapy phases, NSCLC subtypes, and different radiotherapeutic responses. We found that compared to the healthy controls, myelin-associated glycoprotein (MAG), phosphatidylinositol (PI), and phosphatidylserine (PS) were mainly and significantly altered lipid elements (> twofold, and p < 0.05) among NSCLC patients with different radiotherapy phases. Through comparison of lipid elements between bad and good responses of NSCLC patients with radiotherapy, the obviously declined phosphatidylglycerol (PG 18 : 0/14 : 0, 18 : 1/18 : 3, and 18 : 0/20 : 1) or markedly elevated PI (20 : 0/22 : 5 and 18 : 2/22 : 4) and phosphatidic acid (PA 14 : 0/20 : 4, 14 : 0/20 : 3, and 18 : 2/22 : 4) could indicate poor therapeutic response for NSCLC patients. The results of ROC curve analysis suggested that PG (18 : 0/20 : 1 and 18 : 0/14 : 0) could clearly predict the radiotherapeutic response for NSCLC patients, and PS (18 : 0/20 : 0) and cholesterol were the first two lipid components with the most potential for the diagnosis of advanced NSCLC. Our results indicated that plasma lipidomics profiling might have a vital value to uncover the heterogeneity of lipid metabolism in healthy people and advanced NSCLC patients with different radiotherapy phase, and further to screen out radiotherapeutic response-specific biomarkers.

Polyneuropathy in systemic sclerosis: exploring the causes and biomarkers.

Systemic sclerosis (SSc) is a rare autoimmune disease with multiple organ involvement; however, the contribution of the nervous system (NS) remains relatively understudied. There are no specific data on the role of the autoimmune response and inflammation in the development of peripheral nerve system (PNS) damage in SSc and markers to assess this damage have yet to be identified. The primary objective of this study was to define the autoimmune mechanisms that lead to neuropathy by identifying antibodies (Abs) that target certain component of the NS or are associated with SSc. The secondary objective was to identify markers of NS damage that correlate with the detection and progression of polyneuropathy (PNP). This study included patients diagnosed with SSc who met ACR/EULAR 2013 classification criteria at two leading Latvian hospitals between January 2016 and December 2021. Patients underwent a nerve conduction study (NCS). The SSc-associated Abs, Abs against myelin-associated glycoprotein (MAG) and anti-ganglioside Abs (GM1, GM2, GD1a, GD1b and GQ1b) were analysed. Potential serum PNS biomarkers-neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15)-were measured. We recruited 103 Caucasian patients diagnosed with SSc. SSc-associated Abs did not differ significantly between patients with and without PNP (p > 0.05). Anti-MAG and anti-ganglioside Abs in patients with PNP did not present a significant increase above the reference range. NfL, GFAP and GDF15 were significantly elevated in the presence of PNP (p < 0.05), with a moderate to high effect size (r = 0.36-0.65). Our regression analysis revealed a strong association between the HAQ-DI score, older age, male gender and the risk of developing PNP. The development of PNP in patients with SSc is most likely due to ageing, natural progression and the sequelae of the disease. Several serum biomarkers-NfL, GFAP and GDF15-could be used as relevant diagnostic biomarkers for PNP in patients with SSc. Future studies are warranted to validate the diagnostic efficacy of these biomarkers and to unravel the complex interplay of factors leading to PNP in patients with SSc.

A novel cell-based immunofluorescence assay for the detection of autoantibodies to myelin-associated glycoprotein.

Peripheral neuropathy with antibodies to myelin-associated glycoprotein (MAG) is an autoimmune demyelinating disorder of the peripheral nervous system caused by pathogenic IgM recognizing the human natural killer-1 glycoepitope expressed on MAG. This study aimed to analyze the performance of a new indirect immunofluorescence cell-based assay (CBA, EUROIMMUN) for the detection of anti-MAG IgM. Antibody reactivity was determined in sera from 95 patients with clinical and neurophysiological evidence of anti-MAG-associated neuropathy and in control samples from 55 patients with other forms of peripheral neuropathy. Compared to the results of the gold standard method (ELISA, Bühlmann) and using samples at a dilution of 1:100, the CBA had a sensitivity of 98.9% and a specificity of 100% (PPV 100%, NPV 98.2%). In conclusion, the CBA allows the detection of antibodies to MAG using an easy and standardized technique, and it presents a sensitive and specific alternative to the more time-consuming ELISA. Larger studies are needed to address anti-MAG titer monitoring in parallel with clinical activity.

Severe central nervous system demyelination in Sanfilippo disease.

Chronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients. Brain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms. Analyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice. Our findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

Glutamate delta-1 receptor regulates oligodendrocyte progenitor cell differentiation and myelination in normal and demyelinating conditions.

In this study, we investigated the role of glutamate delta 1 receptor (GluD1) in oligodendrocyte progenitor cell (OPC)-mediated myelination during basal (development) and pathophysiological (cuprizone-induced demyelination) conditions. Initially, we sought to determine the expression pattern of GluD1 in OPCs and found a significant colocalization of GluD1 puncta with neuron-glial antigen 2 (NG2, OPC marker) in the motor cortex and dorsal striatum. Importantly, we found that the ablation of GluD1 led to an increase in the number of myelin-associated glycoprotein (MAG+) cells in the corpus callosum and motor cortex at P40 without affecting the number of NG2+ OPCs, suggesting that GluD1 loss selectively facilitates OPC differentiation rather than proliferation. Further, deletion of GluD1 enhanced myelination in the corpus callosum and motor cortex, as indicated by increased myelin basic protein (MBP) staining at P40, suggesting that GluD1 may play an essential role in the developmental regulation of myelination during the critical window period. In contrast, in cuprizone-induced demyelination, we observed reduced MBP staining in the corpus callosum of GluD1 KO mice. Furthermore, cuprizone-fed GluD1 KO mice showed more robust motor deficits. Collectively, our results demonstrate that GluD1 plays a critical role in OPC regulation and myelination in normal and demyelinating conditions.

Axonal regrowth under release ofmyelin-associated glycoprotein: chemotaxis by pioneer Schwann cells andCajal's gigantic clubs.

Myelin-associated glycoprotein (MAG), released from pre-degenerated distal nerves following axotomy, blocks the regrowth of sprouts and naked axons. Ensheathed axons, however, continue to elongate and reach MAG-releasing distal nerves. To determine the regenerative mechanism of ensheathed axons without navigators of axonal growth cones by the film model method, we inserted a MAG-releasing distal nerve segment treated with liquid nitrogen (N2DS) between the two films, facing the proximal end of the common peroneal nerves in mice transected 4 days earlier for axons to become ensheathed. On the third postoperative day (Day 3), axon fascicles, subjected to silver staining, extended toward N2DS but with few branches, forming terminal swellings called Cajal's gigantic clubs (CGCs) that are filled with axonal growth cones. Filter paper wetted with either 250 pg/ml MAG or N2DS showed the same configurations when inserted between the two films. This effect was lost following anti-MAG treatment; fascicles strayed near the parent nerve with numerous branches, formed a net of axons and tapered toward thin tips at their ends, just like controls without N2DS. Schwann cell bundles on Day 3 detected with anti-S100, formed sheaths of CGCs at their ends and connected to pioneer Schwann cells (pSCs). To analyze the physiology of Schwann cells, independent of axons, the parent nerve transected 4 days prior was crushed. On Day 2, with pSCs ahead, Schwann cell bundles extended toward N2DS. On Day 4, main bundles regressed, leaving pSCs motionless. Thus, MAG is a candidate chemoattractant for both pSCs and CGCs.

Breastfeeding promotes oligodendrocyte precursor cells division and myelination in the demyelinated corpus callosum

Demyelination alters the conduction of neuronal signals and hampers sensory-motor functions. Experimental and clinical evidence suggest that breastfeeding exerts a promyelinating impact on the maternal brain. The mechanism underlying this neuroprotective effect is not well-understood. In the present paper, we assessed the impact of rat lactation on lysolecithin-induced demyelination injury within the corpus callosum of lactating and non-lactating postpartum rats. We show that lactation enhanced the cell density of oligodendrocyte precursor cells (OPCs), but not that of activated microglia and astrocytes, within the demyelination lesion. Lactation also increased the expression of myelin markers involved in the initial stage of myelin recovery (Myelin-associated glycoprotein and 2′,3′-cyclic nucleotide 3′-phosphodiesterase) and reduced the demyelination injury. Altogether, these data suggest that lactation creates a conducive promyelinating environment through increased OPCs cell division, enhanced expression of select myelin proteins, and reduced number of non-myelinated axons.

The Fulcrum of Demyelination in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS), including the brain, spinal cord, and optic nerves. The symptoms can vary from muscle weakness to vision loss. In the case of MS, the immune system attacks the myelin sheath, which protects the nerve fiber and causes inflammation resulting in demyelination. The myelin sheath has the composition of various proteins including membrane proteins and glycoproteins. The four main proteins namely Myelin Basic Protein (MBP), Myelin associated Oligodendrocyte Basic protein (MOBP), Myelin Proteolipid Protein (PLP) and Myelin Associated Glycoprotein (MAG) are known to be critical auto-antigens in causing demyelination in CNS leading to MS. Three out of these four proteins are intrinsically disordered proteins and in this review, we attempted to understand how these proteins play a crucial role in maintaining the integrity of myelin, by exploring its structural and functional aspects and also their auto-antigenicity leading to multiple sclerosis.

Anti-myelin-associated glycoprotein neuropathy: Where do we stand?

Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti-MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off-label immunotherapy is common, there are currently no proven effective disease-modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti-MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti-MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti-MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B-cell-depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti-MAG neuropathy patients.

Glycine disrupts myelin, glutamatergic neurotransmission, and redox homeostasis in a neonatal model for non ketotic hyperglycinemia

Non ketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by mutations in the genes encoding glycine cleavage system proteins. Classic NKH has a neonatal onset, and patients present with severe neurodegeneration. Although glycine accumulation has been implicated in NKH pathophysiology, the exact mechanisms underlying the neurological damage and white matter alterations remain unclear. We investigated the effects of glycine in the brain of neonatal rats and MO3.13 oligodendroglial cells. Glycine decreased myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in the corpus callosum and striatum of rats on post-natal day (PND) 15. Glycine also reduced neuroglycan 2 (NG2) and N-methyl-d-aspartate receptor subunit 1 (NR1) in the cerebral cortex and striatum on PND15. Moreover, glycine reduced striatal glutamate aspartate transporter 1 (GLAST) content and neuronal nucleus (NeuN), and increased glial fibrillary acidic protein (GFAP) on PND15. Glycine also increased DCFH oxidation and malondialdehyde levels and decreased GSH concentrations in the cerebral cortex and striatum on PND6, but not on PND15. Glycine further reduced viability but did not alter DCFH oxidation and GSH levels in MO3.13 cells after 48- and 72-h incubation. These data indicate that impairment of myelin structure and glutamatergic system and induction of oxidative stress are involved in the neuropathophysiology of NKH.