The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform
Richard H. Quarles - One of the best experts on this subject based on the ideXlab platform.
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Myelin Associated Glycoprotein mag past present and beyond
Journal of Neurochemistry, 2007Co-Authors: Richard H. QuarlesAbstract:The Myelin-Associated Glycoprotein (MAG) is a type I transmembrane Glycoprotein localized in periaxonal Schwann cell and oligodendroglial membranes of Myelin sheaths where it functions in glia–axon interactions. It contains five immunoglobulin (Ig)-like domains and is in the sialic acid-binding subgroup of the Ig superfamily. It appears to function both as a ligand for an axonal receptor that is needed for the maintenance of Myelinated axons and as a receptor for an axonal signal that promotes the differentiation, maintenance and survival of oligodendrocytes. Its function in the maintenance of Myelinated axons may be related to its role as one of the white matter inhibitors of neurite outgrowth acting through a receptor complex involving the Nogo receptor and/or gangliosides containing 2,3-linked sialic acid. MAG is expressed as two developmentally regulated isoforms with different cytoplasmic domains that may activate different signal transduction pathways in Myelin-forming cells. MAG contains a carbohydrate epitope shared with other glycoconjugates that is a target antigen in autoimmune peripheral neuropathy Associated with IgM gammopathy and has been implicated in a dying back oligodendrogliopathy in multiple sclerosis.
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Myelin‐Associated Glycoprotein (MAG): past, present and beyond
Journal of Neurochemistry, 2007Co-Authors: Richard H. QuarlesAbstract:The Myelin-Associated Glycoprotein (MAG) is a type I transmembrane Glycoprotein localized in periaxonal Schwann cell and oligodendroglial membranes of Myelin sheaths where it functions in glia–axon interactions. It contains five immunoglobulin (Ig)-like domains and is in the sialic acid-binding subgroup of the Ig superfamily. It appears to function both as a ligand for an axonal receptor that is needed for the maintenance of Myelinated axons and as a receptor for an axonal signal that promotes the differentiation, maintenance and survival of oligodendrocytes. Its function in the maintenance of Myelinated axons may be related to its role as one of the white matter inhibitors of neurite outgrowth acting through a receptor complex involving the Nogo receptor and/or gangliosides containing 2,3-linked sialic acid. MAG is expressed as two developmentally regulated isoforms with different cytoplasmic domains that may activate different signal transduction pathways in Myelin-forming cells. MAG contains a carbohydrate epitope shared with other glycoconjugates that is a target antigen in autoimmune peripheral neuropathy Associated with IgM gammopathy and has been implicated in a dying back oligodendrogliopathy in multiple sclerosis.
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Jimpy mice: quantitation of Myelin-Associated Glycoprotein and other proteins.
Journal of Neurochemistry, 2006Co-Authors: Katsuhiko Yanagisawa, Richard H. QuarlesAbstract:: Myelin-Associated Glycoprotein (MAG), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) activity, Myelin basic protein (BP), and proteolipid protein (PLP) were quantitated in the brains of 20-day-old Jimpy and control mice. The levels of MAG, CNPase, and BP in Jimpy brains were 5.3%, 9.7%, and 1.9% of those in control brains, respectively. Immunoblotting analysis did not reveal an increased apparent Mr for MAG in the Jimpy mouse, as has been observed in some other hypoMyelinating murine mutants. PLP was reduced more than the other proteins, as it was not detected by an immunoblotting technique that was capable of detecting 0.5% of the control level.
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Distribution of P0 protein and the Myelin-Associated Glycoprotein in peripheral nerves from Trembler mice.
Journal of Neurocytology, 1991Co-Authors: J. W. Heath, Richard H. Quarles, Takashi Inuzuka, B. D. TrappAbstract:The Trembler mouse has a dysymelination of peripheral nerves that includes hypoMyelination, failure of Myelin compaction, and deMyelination/reMyelination. We have localized the Myelin proteins P0 and Myelin Associated Glycoprotein in Trembler peripheral nerve and correlated their distributions with the ultrastructure of Myelin internodes. Immunocytochemically, Myelin-Associated Glycoprotein was localized in Schwann cell periaxonal membranes, Schmidt-Lanterman incisures, paranodal loops, and internal and external mesaxons. P0 staining was located over compact Myelin and regions of Schwann cell cytoplasm rich in Golgi membranes. An unusual abundance of small, P0-stained, Golgi-related vesicles was found in some Schwann cells. P0 protein was also detected in multiple spiral wraps of Myelin-Associated Glycoprotein-positive mesaxon membranes. At some sites the periodicity of the Myelin membranes was intermediate to that found in mesaxon membranes and compact Myelin. The distance between apposing extracellular leaflets was similar to that found in mesaxon membranes, while the cytoplasmic leaflets were fused but twice as thick as normal major dense lines. These intermediate membranes were stained by P0 and Myelin-Associated Glycoprotein antiserum. These studies suggest that altered transport and/or translocation of P0 and Myelin-Associated Glycoprotein results in defective Myelin compaction in Trembler peripheral nerve.
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The Myelin-Associated Glycoprotein is phosphorylated in the peripheral nervous system.
Biochemical and Biophysical Research Communications, 1990Co-Authors: Harish C. Agrawal, Antonio Noronha, Daya Agrawal, Richard H. QuarlesAbstract:Abstract Phosphorylation of the Myelin-Associated Glycoprotein (MAG) in the peripheral nervous system is demonstrated by immunoprecipitation from Myelin proteins radiolabeled in vivo , in nerve slices and in a cell-free system. Phosphoamino acid analysis of immuno-precipitated MAG revealed the presence of radioactivity in phosphoserine, but not in phosphothreonine or phosphotyrosine. Only the shorter isoform of MAG (S-MAG) was detected by immunostaining of nitrocellulose sheets with anti-MAG anti-serum after enzymatic deglycosylation of immunoprecipitated MAG labeled in nerve slices. Autoradiography of the same Western blots revealed that most of the radioactive phosphate was in S-MAG, demonstrating that the polypeptide backbone of S-MAG is phosphorylated in the PNS.
Marie T Filbin - One of the best experts on this subject based on the ideXlab platform.
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Myelin Associated Glycoprotein inhibits schwann cell migration and induces their death
The Journal of Neuroscience, 2017Co-Authors: Nagarathnamma Chaudhry, Corinne Bachelin, Violetta Zujovic, Melissa Hilaire, Katherine T Baldwin, Rose M Follis, Roman J Giger, Bruce D Carter, Anne Baronvan Evercooren, Marie T FilbinAbstract:ReMyelination of central nervous system (CNS) axons by Schwann cells (SC) is not efficient, in part due to their poor migration into the adult CNS. Although it is known that migrating SC avoid white matter tracts, the molecular mechanisms underlying this exclusion has never been elucidated. We now demonstrate that Myelin-Associated Glycoprotein (MAG), a well-known inhibitor of neurite outgrowth, inhibits rat SC migration and induces their death via γ secretase-dependent regulated intramembrane proteolysis (RIP) of the p75 neurotrophin receptor (also known as p75 cleavage). Blocking p75 cleavage using inhibitor X (Inh X), a compound that inhibits γ-secretase activity before exposing to MAG or CNS Myelin improves SC migration and survival in vitro . Furthermore, mouse SC pre-treated with Inh X migrate extensively in the deMyelinated mouse spinal cord and re-Myelinate axons. These results suggest a novel role for MAG/Myelin in poor SC-Myelin interaction and identify p75 cleavage as a mechanism that can be therapeutically targeted to enhance SC-mediated axon reMyelination in the adult CNS. SIGNIFICANCE STATEMENT Numerous studies have used Schwann cells, the Myelin-making cells of the peripheral nervous system (PNS) to reMyelinate adult central nervous system (CNS) axons. Indeed, these transplanted cells successfully reMyelinate axons, but unfortunately they do not migrate far and so reMyelinate only a few axons in the vicinity of the transplant site. It is believed that if Schwann cells could be induced to migrate further and survive better, they may represent a valid therapy for reMyelination. We show that Myelin-Associated Glycoprotein (MAG) or CNS Myelin in general, inhibit rodent Schwann cell migration and induce their death via cleavage of the neurotrophin receptor, p75. Blockade of p75 cleavage using a specific inhibitor significantly improves migration and survival of the transplanted Schwann cells in vivo .
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soluble Myelin Associated Glycoprotein mag found in vivo inhibits axonal regeneration
Molecular and Cellular Neuroscience, 1997Co-Authors: Song Tang, Patrick Doherty, Frank S Walsh, Robert W Woodhall, Ying Jing Shen, Maria Elena Debellard, Jane L Saffell, Marie T FilbinAbstract:Myelin-Associated Glycoprotein (MAG) is a potent inhibitor of axonal regeneration when used as a substrate for growth. However, to be characterized definitively as inhibitory rather than nonpermissive, MAG must also inhibit axonal regeneration when presented in solution. Here, we show that soluble dMAG (extracellular domain only), released in abundance from Myelin and foundin vivoand chimeric MAG-Fc, can potently inhibit axonal regeneration. For both dMAG and MAG-Fc, inhibition is dose-dependent. If Myelin-conditioned medium is immunodepleted of dMAG, or if a MAG antibody is included with MAG-Fc, inhibition is completely neutralized. Together with MAG's ability to induce growth cone collapse, these results demonstrate that MAG is an inhibitory molecule and not merely nonpermissive. The results also suggest that MAG binds to a specific receptor and initiates a signal transduction cascade to effect inhibition. Importantly, these results indicate that soluble dMAG detectedin vivocould contribute to the lack of regeneration in the mammalian CNS after injury.
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Myelin-Associated Glycoprotein: a role in Myelination and in the inhibition of axonal regeneration?
Current Opinion in Neurobiology, 1995Co-Authors: Marie T FilbinAbstract:Inhibitory molecules in CNS Myelin affect axonal regeneration after injury. In the past year, Myelin-Associated Glycoprotein (MAG), a well-characterized Myelin protein, has been identified as an inhibitor of axonal regeneration. This finding, together with its established ability to promote outgrowth, defines MAG as a bifunctional molecule. MAG has also been included in a family of sialic acid binding proteins, providing a clue to the identity of the MAG receptor. MAG knockout mice reveal that MAG is not essential for the initiation of Myelination; however, it plays an important role in maintaining a stable interaction between axons and Myelin.
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sialoadhesin Myelin Associated Glycoprotein and cd22 define a new family of sialic acid dependent adhesion molecules of the immunoglobulin superfamily
Current Biology, 1994Co-Authors: Sorge Kelm, Andrea Pelz, Roland Schauer, Marie T Filbin, Song Tang, Maria Elena De Bellard, Ronald L Schnaar, James A Mahoney, Adele Hartnell, Paul F BradfieldAbstract:Abstract Background: Protein–carbohydrate interactions are believed to be important in many biological processes that involve cell–cell communication. Apart from the selectins, the only well-characterized vertebrate sialic acid-dependent adhesion molecules are CD22 and sialoadhesin; CD22 is a member of the immunoglobulin superfamily that is expressed by B lymphocytes and sialoadhesin is a macrophage receptor. The recent cloning of the gene encoding sialoadhesin has shown that it is also immunoglobulin-like. Both proteins share sequence similarity with the Myelin-Associated Glycoprotein, an adhesion molecule of oligodendrocytes and Schwann cells that has been implicated in the process of Myelination, raising the important question of whether Myelin-Associated Glycoprotein is also a sialic acid-binding protein. Results We have investigated the binding properties of these three receptors when expressed either in monkey COS cells or as chimaeric proteins containing the Fc portion of human immunoglobulin G. We demonstrate that, like sialoadhesin and CD22, Myelin-Associated Glycoprotein mediates cell adhesion by binding to cell-surface glycans that contain sialic acid. We have dissected the specificities of these three adhesins further: whereas sialoadhesin binds equally to the sugar moieties NeuAc α 2→3Gal β 1→3(4)GlcNAc or NeuAc α 2→3Gal β 1→3GalNAc, Myelin-Associated Glycoprotein recognizes only NeuAc α 2→3Gal β 1→3GalNAc and CD22 binds specifically to NeuAc α 2→6Gal β 1→4GlcNAc. Furthermore, we show that the recognition of sialylated glycans on the surfaces of particular cell types leads to the selective binding of sialoadhesin to neutrophils, Myelin-Associated Glycoprotein to neurons and CD22 to lymphocytes. Conclusion Our findings demonstrate that a subgroup of the immunoglobulin superfamily can mediate diverse biological processes through recognition of specific sialylated glycans on cell surfaces. We propose that this subgroup of proteins be called the sialoadhesin family.
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a novel role for Myelin Associated Glycoprotein as an inhibitor of axonal regeneration
Neuron, 1994Co-Authors: Gitali Mukhopadhyay, Patrick Doherty, Frank S Walsh, Paul R Crocker, Marie T FilbinAbstract:Abstract Following nerve injury, axons in the CNS do not normally regenerate. It has been shown that CNS Myelin inhibits neurite outgrowth, though the nature of the molecules responsible for this effect are not known. Here, we demonstrate that the Myelin-Associated Glycoprotein (MAG), a transmembrane protein of both CNS and PNS Myelin, strongly inhibits neurite outgrowth from both developing cerebellar and adult dorsal root ganglion (DRG) neurons in vitro. This inhibition is reversed by an antiMAG antibody. In contrast, MAG promotes neurite outgrowth from newborn DRG neurons. These results suggest that MAG may be responsible, in part, for the lack of CNS nerve regeneration in vivo and may influence, both temporally and spatially, regeneration in the PNS.
Ronald L Schnaar - One of the best experts on this subject based on the ideXlab platform.
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Myelin Associated Glycoprotein protects neurons from excitotoxicity
Journal of Neurochemistry, 2011Co-Authors: Pablo H H Lopez, Niraj R Mehta, Abdullah Shafique Ahmad, Mayu Toner, Elizabeth Rowland, Jiangyang Zhang, Sylvain Dore, Ronald L SchnaarAbstract:In addition to supporting rapid nerve conduction, Myelination nurtures and stabilizes axons and protects them from acute toxic insults. One Myelin molecule that protects and sustains axons is Myelin-Associated Glycoprotein (MAG). MAG is expressed on the innermost wrap of Myelin, apposed to the axon surface, where it interacts with axonal receptors that reside in lateral membrane domains including gangliosides, the GPI-anchored Nogo receptors, and β1-integrin. We report here that MAG protection extends beyond the axon to the neurons from which those axons emanate, protecting them from excitotoxicity. Compared to wild type mice, Mag-null mice displayed markedly increased seizure activity in response to intraperitoneal injection of kainic acid, an excitotoxic glutamate receptor agonist. Mag-null mice also had larger lesion volumes in response to intrastriatal injection of the excitotoxin N-methyl-D-aspartate (NMDA). Prior injection of a soluble form of MAG partially protected Mag-null mice from NMDA-induced lesions. Hippocampal neurons plated on proteins extracted from wild-type rat or mouse Myelin were resistant to kainic acid-induced excitotoxicity, whereas neurons plated on proteins from Mag-null Myelin were not. Protection was reversed by anti-MAG antibody and replicated by addition of soluble MAG. MAG-mediated protection from excitotoxicity was dependent on Nogo receptors and β1-integrin. We conclude that MAG engages membrane-domain resident neuronal receptors to protect neurons from excitotoxicity, and that soluble MAG mitigates excitotoxic damage in vivo.
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Myelin Associated Glycoprotein and its axonal receptors
Journal of Neuroscience Research, 2009Co-Authors: Ronald L Schnaar, Pablo H H LopezAbstract:Myelin-Associated Glycoprotein (MAG) is expressed on the innermost Myelin membrane wrap, directly apposed to the axon surface. Although it is not required for Myelination, MAG enhances long-term axon-Myelin stability, helps to structure nodes of Ranvier, and regulates the axon cytoskeleton. In addition to its role in axon-Myelin stabilization, MAG inhibits axon regeneration after injury; MAG and a discrete set of other molecules on residual Myelin membranes at injury sites actively signal axons to halt elongation. Both the stabilizing and the axon outgrowth inhibitory effects of MAG are mediated by complementary MAG receptors on the axon surface. Two MAG receptor families have been described, sialoglycans (specifically gangliosides GD1a and GT1b) and Nogo receptors (NgRs). Controversies remain about which receptor(s) mediates which of MAG's biological effects. Here we review the findings and challenges in associating MAG's biological effects with specific receptors.
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Myelin‐Associated Glycoprotein and its axonal receptors
Journal of Neuroscience Research, 2009Co-Authors: Ronald L Schnaar, Pablo H H LopezAbstract:Myelin-Associated Glycoprotein (MAG) is expressed on the innermost Myelin membrane wrap, directly apposed to the axon surface. Although it is not required for Myelination, MAG enhances long-term axon-Myelin stability, helps to structure nodes of Ranvier, and regulates the axon cytoskeleton. In addition to its role in axon-Myelin stabilization, MAG inhibits axon regeneration after injury; MAG and a discrete set of other molecules on residual Myelin membranes at injury sites actively signal axons to halt elongation. Both the stabilizing and the axon outgrowth inhibitory effects of MAG are mediated by complementary MAG receptors on the axon surface. Two MAG receptor families have been described, sialoglycans (specifically gangliosides GD1a and GT1b) and Nogo receptors (NgRs). Controversies remain about which receptor(s) mediates which of MAG's biological effects. Here we review the findings and challenges in associating MAG's biological effects with specific receptors.
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axonal protective effects of the Myelin Associated Glycoprotein
The Journal of Neuroscience, 2009Co-Authors: Thien Nguyen, Ronald L Schnaar, Niraj R Mehta, Katherine Conant, Melina V Jones, Peter A Calabresi, Giorgia Melli, Ahmet Hoke, Guo Li Ming, Hongjun SongAbstract:Progressive axonal degeneration follows deMyelination in many neurological diseases, including multiple sclerosis and inherited deMyelinating neuropathies, such as Charcot-Marie-Tooth disease. One glial molecule, the Myelin-Associated Glycoprotein (MAG), located in the adaxonal plasmalemma of Myelin-producing cells, is known to signal to the axon and to modulate axonal caliber through phosphorylation of axonal neurofilament proteins. This report establishes for the first time that MAG also promotes resistance to axonal injury and prevents axonal degeneration both in cell culture and in vivo. This effect on axonal stability depends on the RGD domain around arginine 118 in the extracellular portion of MAG, but it is independent of Nogo signaling in the axon. Exploiting this pathway may lead to therapeutic strategies for neurological diseases characterized by axonal loss.
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sialoadhesin Myelin Associated Glycoprotein and cd22 define a new family of sialic acid dependent adhesion molecules of the immunoglobulin superfamily
Current Biology, 1994Co-Authors: Sorge Kelm, Andrea Pelz, Roland Schauer, Marie T Filbin, Song Tang, Maria Elena De Bellard, Ronald L Schnaar, James A Mahoney, Adele Hartnell, Paul F BradfieldAbstract:Abstract Background: Protein–carbohydrate interactions are believed to be important in many biological processes that involve cell–cell communication. Apart from the selectins, the only well-characterized vertebrate sialic acid-dependent adhesion molecules are CD22 and sialoadhesin; CD22 is a member of the immunoglobulin superfamily that is expressed by B lymphocytes and sialoadhesin is a macrophage receptor. The recent cloning of the gene encoding sialoadhesin has shown that it is also immunoglobulin-like. Both proteins share sequence similarity with the Myelin-Associated Glycoprotein, an adhesion molecule of oligodendrocytes and Schwann cells that has been implicated in the process of Myelination, raising the important question of whether Myelin-Associated Glycoprotein is also a sialic acid-binding protein. Results We have investigated the binding properties of these three receptors when expressed either in monkey COS cells or as chimaeric proteins containing the Fc portion of human immunoglobulin G. We demonstrate that, like sialoadhesin and CD22, Myelin-Associated Glycoprotein mediates cell adhesion by binding to cell-surface glycans that contain sialic acid. We have dissected the specificities of these three adhesins further: whereas sialoadhesin binds equally to the sugar moieties NeuAc α 2→3Gal β 1→3(4)GlcNAc or NeuAc α 2→3Gal β 1→3GalNAc, Myelin-Associated Glycoprotein recognizes only NeuAc α 2→3Gal β 1→3GalNAc and CD22 binds specifically to NeuAc α 2→6Gal β 1→4GlcNAc. Furthermore, we show that the recognition of sialylated glycans on the surfaces of particular cell types leads to the selective binding of sialoadhesin to neutrophils, Myelin-Associated Glycoprotein to neurons and CD22 to lymphocytes. Conclusion Our findings demonstrate that a subgroup of the immunoglobulin superfamily can mediate diverse biological processes through recognition of specific sialylated glycans on cell surfaces. We propose that this subgroup of proteins be called the sialoadhesin family.
M P Lunn - One of the best experts on this subject based on the ideXlab platform.
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Immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-Associated peripheral neuropathies.
The Cochrane database of systematic reviews, 2020Co-Authors: M P Lunn, E. Nobile-orazioAbstract:Serum monoclonal anti-Myelin Associated Glycoprotein antibodies may be pathogenic in some patients with IgM paraprotein and deMyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be of benefit in the treatment of the neuropathy. Many potential therapies have been described in small trials, uncontrolled studies and case reports. To examine the efficacy of any form of immunotherapy in reducing disability and impairment resulting from IgM anti-Myelin Associated Glycoprotein paraprotein-Associated deMyelinating peripheral neuropathy. We searched the Cochrane Neuromuscular Disease Group register (August 2002) and MEDLINE (January 1966 - August 2002) and EMBASE (January 1980 - August 2002) for controlled trials, checked the bibliographies to identify other controlled trials and contacted authors and other experts in the field. Types of studies: randomised or quasi-randomised controlled trials. patients of any age with anti-Myelin Associated Glycoprotein antibody Associated deMyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance of any severity. Types of interventions: any type of immunotherapy. Types of outcome measures: Primary: improvement in the Neuropathy Disability Score or Modified Rankin Scale six months after randomisation Secondary: Neuropathy Disability Score and/or the Modified Rankin Score 12 months after randomisation. Ten metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation. IgM paraprotein levels and anti-Myelin Associated Glycoprotein antibody titres six months after randomisation. Adverse effects of treatments. We identified six randomised controlled trials of which five were included after discussion between the authors. One author extracted the data and the other checked them. No missing data could be obtained from authors. The five eligible trials used four of the many available immunotherapy treatments. Only two had comparable interventions and outcomes but these were only short-term studies. There were no significant benefits of the treatments used in the predefined outcomes. However intravenous immunoglobulin showed benefits in terms of improved Modified Rankin Scale at two weeks and 10 metre walk time at four weeks. Serious adverse effects of intravenous immunoglobulin are known to occur from observational studies but none were encountered in these trials. There is inadequate reliable evidence from trials of immunotherapies in anti-Myelin Associated Glycoprotein paraproteinaemic neuropathy to recommend any particular immunotherapy treatment. Intravenous immunoglobulin is relatively safe and may produce some short-term benefit. Large well designed randomised trials are required to assess the efficacy of promising new therapies.
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immunotherapy for igm anti Myelin Associated Glycoprotein paraprotein Associated peripheral neuropathies
Cochrane Database of Systematic Reviews, 2016Co-Authors: M P Lunn, E NobileorazioAbstract:BACKGROUND: Serum monoclonal anti-Myelin-Associated Glycoprotein antibodies may be pathogenic in some people with immunoglobulin M (IgM) paraprotein and deMyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. This is an update of a review first published in 2003 and previously updated in 2006. OBJECTIVES: To assess the effects of immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-Associated deMyelinating peripheral neuropathy. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register 6 June 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011) for controlled trials. We also checked bibliographies and contacted authors and experts in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials involving participants of any age treated with any type of immunotherapy for anti-Myelin-Associated Glycoprotein antibody-Associated deMyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity.Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisation. Secondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; 10-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-Myelin-Associated Glycoprotein antibody titres at six months after randomisation; and adverse effects of treatments. DATA COLLECTION AND ANALYSIS: The two authors independently selected studies. Two authors independently assessed the risk of bias in included studies. MAIN RESULTS: We identified seven eligible trials (182 participants), which tested intravenous immunoglobulin, alfa interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Only two trials, of intravenous immunoglobulin (with 33 participants, including 20 with antibodies against Myelin-Associated Glycoprotein), had comparable interventions and outcomes, but both were short-term trials.There were no clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed a statistical benefit in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Cyclophosphamide failed to show any benefit in the trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. A trial of rituximab was of poor methodological quality with a high risk of bias and a further larger study is awaited. Serious adverse events were few in the other trials. AUTHORS' CONCLUSIONS: There is inadequate reliable evidence from trials of immunotherapies in anti-Myelin-Associated Glycoprotein paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. Large well designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies, preferably employing unified, consistent, well designed, responsive and valid outcome measures.
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The Cochrane Library - Immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-Associated peripheral neuropathies.
Cochrane Database of Systematic Reviews, 2012Co-Authors: M P Lunn, Eduardo Nobile-orazioAbstract:BACKGROUND: Serum monoclonal anti-Myelin-Associated Glycoprotein antibodies may be pathogenic in some people with immunoglobulin M (IgM) paraprotein and deMyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. This is an update of a review first published in 2003 and previously updated in 2006. OBJECTIVES: To assess the effects of immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-Associated deMyelinating peripheral neuropathy. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register 6 June 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011) for controlled trials. We also checked bibliographies and contacted authors and experts in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials involving participants of any age treated with any type of immunotherapy for anti-Myelin-Associated Glycoprotein antibody-Associated deMyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity.Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisation. Secondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; 10-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-Myelin-Associated Glycoprotein antibody titres at six months after randomisation; and adverse effects of treatments. DATA COLLECTION AND ANALYSIS: The two authors independently selected studies. Two authors independently assessed the risk of bias in included studies. MAIN RESULTS: We identified seven eligible trials (182 participants), which tested intravenous immunoglobulin, alfa interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Only two trials, of intravenous immunoglobulin (with 33 participants, including 20 with antibodies against Myelin-Associated Glycoprotein), had comparable interventions and outcomes, but both were short-term trials.There were no clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed a statistical benefit in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Cyclophosphamide failed to show any benefit in the trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. A trial of rituximab was of poor methodological quality with a high risk of bias and a further larger study is awaited. Serious adverse events were few in the other trials. AUTHORS' CONCLUSIONS: There is inadequate reliable evidence from trials of immunotherapies in anti-Myelin-Associated Glycoprotein paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. Large well designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies, preferably employing unified, consistent, well designed, responsive and valid outcome measures.
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Immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-Associated peripheral neuropathies.
The Cochrane database of systematic reviews, 2006Co-Authors: M P Lunn, E. Nobile-orazioAbstract:Serum monoclonal anti-Myelin Associated Glycoprotein antibodies may be pathogenic in some people with IgM paraprotein and deMyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. To examine the efficacy of any form of immunotherapy in reducing disability and impairment resulting from IgM anti-Myelin Associated Glycoprotein paraprotein-Associated deMyelinating peripheral neuropathy. We searched the Cochrane Neuromuscular Disease Group Register (March 2005), MEDLINE (January 1966 to March 2005) and EMBASE (January 1980 to March 2005) for controlled trials. We also checked bibliographies and contacted authors and experts in the field. We included randomised or quasi-randomised controlled trials of participants of any age treated with any type of immunotherapy for anti-Myelin-Associated Glycoprotein antibody Associated deMyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance of any severity. Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisationSecondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; ten-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-Myelin Associated Glycoprotein antibody titres at six months after randomisation and adverse effects of treatments. We identified eight possible trials. Of these, five randomised controlled trials were included after discussion between the authors. One author extracted and the other checked the data. No missing data could be obtained from trial authors. The five eligible trials (97 participants) tested intravenous immunoglobulin, interferon-alpha or plasma exchange. Only two, of intravenous immunoglobulin, had comparable interventions and outcomes but both were short-term. There were no significant benefits of the treatments used in the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed benefits in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Serious adverse effects of intravenous immunoglobulin are known to occur from observational studies but none were encountered in these trials. There is inadequate reliable evidence from trials of immunotherapies in anti-Myelin Associated Glycoprotein paraproteinaemic neuropathy to recommend any particular immunotherapy treatment. Intravenous immunoglobulin is relatively safe and may produce some short-term benefit. Large well-designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies.
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anti Myelin Associated Glycoprotein antibodies alter neurofilament spacing
Brain, 2002Co-Authors: M P Lunn, John W Griffin, Thomas O Crawford, R A C Hughes, Kazim A SheikhAbstract:Axon calibre is crucial to efficient impulse transmission in the peripheral nervous system. Neurofilament numbers determine gross axonal diameter, but intra‐axonal distribution depends on the phosphorylation status of neurofilament sidearms. Myelin‐Associated Glycoprotein (MAG) has been implicated in the signalling cascade controlling neurofilament phosphorylation and hence in the control of axon calibre. In an electron microscopic morphometric study we measured nearest neighbour neurofilament distances (NNND) in the axons of sural nerves from patients with anti‐MAG paraproteinaemic neuropathies and compared these with normal human sural nerves and those from patients with Guillain–Barre syndrome or chronic inflammatory deMyelinating polyradiculoneuropathy. Axon calibre was similar in all groups. In normal human sural nerves, axonal NNND was correlated with axonal diameter ( r = 0.56). In diseased axons this correlation did not exist. The NNND was significantly reduced in deMyelinated axons (30.5 2.2 nm) and those with widely spaced Myelin (28.9 1.3 nm) from patients with anti‐MAG antibodies compared with normal axons from normal patients (39.8 3.2 nm) or those with deMyelinating neuropathy (35.8 4.6 nm). This reinforces the hypothesis that MAG is involved in the control of neurofilament spacing through sidearm phosphorylation and demonstrates a MAG‐mediated pathogenic effect of the anti‐MAG antibody in peripheral nerves.
B. D. Trapp - One of the best experts on this subject based on the ideXlab platform.
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Myelin-Associated Glycoprotein
Cell Biology and Pathology of Myelin, 1997Co-Authors: B. D. TrappAbstract:The Myelin-Associated Glycoprotein (MAG) is quantitatively a minor constituent of the total protein found in Myelin isolated from the central (≈1.0%) and peripheral (≈0.1%) nervous systems (Quarles et al. 1973a; Figlewicz et al. 1981). MAG has an apparent molecular weight of 100kD, of which 30% is carbohydrate. Although its precise function is unknown, it is generally accepted that as a member of the immunoglobulin gene superfamily, MAG functions in membrane-membrane interactions. Based on its biochemical properties and enrichment in periaxonal membranes, MAG was initially considered important to the initiation and progression of Myelination. The production of MAG-deficient mice, however, established that Myelination can occur in the absence of MAG (Montag et al. 1994; Li et al. 1994). Recently several laboratories (Mukhopadhyay et al. 1994; McKerracher et al. 1994; Schafer et al. 1996) have provided evidence that MAG can inhibit axonal regeneration. These data raise the possibility that MAG functions as a ligand that regulates axonal properties (Filbin, 1995).
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Myelination in the absence of Myelin Associated Glycoprotein
Nature, 1994Co-Authors: Chumei Li, B. D. Trapp, Michael B. Tropak, Robert Gerlai, S Clapoff, Wanda Abramownewerly, Alan C Peterson, John C. RoderAbstract:THE hypothesis that Myelin-Associated Glycoprotein (MAG) initiates Myelin formation is based in part on observations that MAG has an adhesive role in interactions between oligodendrocytes and neurons1. Furthermore, the over- or underexpression of MAG in transfected Schwann cells in vitro leads to accelerated Myelination2 or hypoMyelination3, respectively. Here we test this idea by creating a null mutation in the mag locus and deriving mice that are totally deficient in MAG expression at the RNA and protein level. In adult mutant animals the degree of Myelination and its compaction are normal, whereas the organization of the periaxonal region is partially impaired. Mutant animals show a subtle intention tremor. Our findings do not support the widely held view that MAG is critical for Myelin formation but rather indicate that MAG is necessary for maintenance of the cytoplasmic collar and periaxonal space of Myelinated fibres.
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Distribution of P_0 protein and the Myelin-Associated Glycoprotein in peripheral nerves from Trembler mice
Journal of Neurocytology, 1991Co-Authors: J. W. Heath, T. Inuzuka, R. H. Quarles, B. D. TrappAbstract:The Trembler mouse has a dysymelination of peripheral nerves that includes hypoMyelination, failure of Myelin compaction, and deMyelination/reMyelination. We have localized the Myelin proteins P_0 and Myelin Associated Glycoprotein in Trembler peripheral nerve and correlated their distributions with the ultrastructure of Myelin internodes. Immunocytochemically, Myelin-Associated Glycoprotein was localized in Schwann cell periaxonal membranes, Schmidt-Lanterman incisures, paranodal loops, and internal and external mesaxons. P_0 staining was located over compact Myelin and regions of Schwann cell cytoplasm rich in Golgi membranes. An unusual abundance of small, P_0-stained, Golgi-related vesicles was found in some Schwann cells. P_0 protein was also detected in multiple spiral wraps of Myelin-Associated Glycoprotein-positive mesaxon membranes. At some sites the periodicity of the Myelin membranes was intermediate to that found in mesaxon membranes and compact Myelin. The distance between apposing extracellular leaflets was similar to that found in mesaxon membranes, while the cytoplasmic leaflets were fused but twice as thick as normal major dense lines. These intermediate membranes were stained by P_0 and Myelin-Associated Glycoprotein antiserum. These studies suggest that altered transport and/or translocation of P_0 and Myelin-Associated Glycoprotein results in defective Myelin compaction in Trembler peripheral nerve.
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Distribution of P0 protein and the Myelin-Associated Glycoprotein in peripheral nerves from Trembler mice.
Journal of Neurocytology, 1991Co-Authors: J. W. Heath, Richard H. Quarles, Takashi Inuzuka, B. D. TrappAbstract:The Trembler mouse has a dysymelination of peripheral nerves that includes hypoMyelination, failure of Myelin compaction, and deMyelination/reMyelination. We have localized the Myelin proteins P0 and Myelin Associated Glycoprotein in Trembler peripheral nerve and correlated their distributions with the ultrastructure of Myelin internodes. Immunocytochemically, Myelin-Associated Glycoprotein was localized in Schwann cell periaxonal membranes, Schmidt-Lanterman incisures, paranodal loops, and internal and external mesaxons. P0 staining was located over compact Myelin and regions of Schwann cell cytoplasm rich in Golgi membranes. An unusual abundance of small, P0-stained, Golgi-related vesicles was found in some Schwann cells. P0 protein was also detected in multiple spiral wraps of Myelin-Associated Glycoprotein-positive mesaxon membranes. At some sites the periodicity of the Myelin membranes was intermediate to that found in mesaxon membranes and compact Myelin. The distance between apposing extracellular leaflets was similar to that found in mesaxon membranes, while the cytoplasmic leaflets were fused but twice as thick as normal major dense lines. These intermediate membranes were stained by P0 and Myelin-Associated Glycoprotein antiserum. These studies suggest that altered transport and/or translocation of P0 and Myelin-Associated Glycoprotein results in defective Myelin compaction in Trembler peripheral nerve.
