The Experts below are selected from a list of 219 Experts worldwide ranked by ideXlab platform
Alex L. Mackay - One of the best experts on this subject based on the ideXlab platform.
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Magnetic Resonance of Myelin Water: An in vivo Marker for Myelin.
Brain plasticity (Amsterdam Netherlands), 2016Co-Authors: Alex L. Mackay, Cornelia LauleAbstract:Myelin is critical for healthy brain function. An accurate in vivo measure of Myelin content has important implications for understanding brain plasticity and neurodegenerative diseases. Myelin water imaging is a magnetic resonance imaging method which can be used to visualize Myelination in the brain and spinal cord in vivo. This review presents an overview of Myelin water imaging data acquisition and analysis, post-mortem validation work, findings in both animal and human studies and a brief discussion about other MR techniques purported to provide in vivo Myelin content. Multi-echo T2 relaxation approaches continue to undergo development and whole-brain imaging time now takes less than 10 minutes; the standard analysis method for this type of data acquisition is a non-negative least squares approach. Alternate methods including the multi-flip angle gradient echo mcDESPOT are also being used for Myelin water imaging. Histological validation studies in animal and human brain and spinal cord tissue demonstrate high specificity of Myelin water imaging for Myelin. Potential confounding factors for in vivo Myelin water fraction measurement include the presence of Myelin debris and magnetization exchange processes. Myelin water imaging has successfully been used to study animal models of injury, applied in healthy human controls and can be used to assess damage and injury in conditions such as multiple sclerosis, neuromyelitis optica, schizophrenia, phenylketonuria, neurofibromatosis, niemann pick’s disease, stroke and concussion. Other quantitative magnetic resonance approaches that are sensitive to, but not specific for, Myelin exist including magnetization transfer, diffusion tensor imaging and T1 weighted imaging.
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Myelin water imaging in multiple sclerosis quantitative correlations with histopathology
Multiple Sclerosis Journal, 2006Co-Authors: Cornelia Laule, Alex L. Mackay, D W Paty, Esther Leung, D K B Lis, Anthony Traboulsee, G R W MooreAbstract:Various magnetic resonance (MR) techniques are used to study the pathological evolution of deMyelinating diseases, such as multiple sclerosis (MS). However, few studies have validated MR derived measurements with histopathology. Here, we determine the correlation of Myelin water imaging, an MR measure of Myelin content, with quantitative histopathologic measures of Myelin density. The multi-component T2 distribution of water was determined from 25 formalin-fixed MS brain samples using a multi-echo T2 relaxation MR experiment. The Myelin water fraction (MWF), defined as T2 signal below 30 milliseconds divided by the total signal, was determined for various regions of interest and compared to Luxol fast blue (Myelin stain) mean optical density (OD) for each sample. MWF had a strong correlation with Myelin stain [mean (range) R2 = 0.67 (0.45-0.92)], validating MWF as a measure of Myelin density. This quantitative technique has many practical applications for the in vivo monitoring of deMyelination and reMyelination in a variety of disorders of Myelin.
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eMagRes - Myelin Water Imaging
eMagRes, 1996Co-Authors: Alex L. Mackay, Cornelia LauleAbstract:The ability to measure Myelin in vivo has great consequences for furthering our knowledge of normal development, as well as for understanding a wide range of neurologic disorders. Measurements of the spin-spin relaxation decay curve in white matter reveal a short T2 component arising from water compartmentalized in the Myelin sheaths of neuronal axons. This signal can be separated from the rest of the signal in white matter to produce Myelin water images. This article begins with a description of the structure and function of Myelin and provides a motivation for imaging Myelin in vivo. We then summarize the current state of Myelin water imaging using magnetic resonance (MR). Fundamental studies involving peripheral nerve and MR/histology comparisons have aided in the interpretation and validation of Myelin water imaging. Finally, we highlight a number of important findings related to Myelin development, damage, and repair. Keywords: Myelin; Myelin water; T2 relaxation; brain; spinal cord; white matter; deMyelination; peripheral nerve; histology
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in vivo visualization of Myelin water in brain by magnetic resonance
Magnetic Resonance in Medicine, 1994Co-Authors: Alex L. Mackay, Kenneth P Whittall, Julian Adler, D W Paty, D A GraebAbstract:We exploit the intrinsic difference in magnetic resonance spin-spin relaxation time, T2, between water associated with Myelin sheaths and water in other central nervous system tissue in order to measure Myelin water content within any region of an image or to generate indirectly a Myelin map of the brain. In normal volunteers, Myelin water maps give the expected Myelin distribution. In multiple sclerosis patients, lesions exhibit different Myelin water contents providing insight into the deMyelination process unavailable from conventional magnetic resonance images. In vivo Myelin measurement has important applications in the clinical management of multiple sclerosis and other white matter diseases.
Nicolas Snaidero - One of the best experts on this subject based on the ideXlab platform.
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Myelin replacement triggered by single-cell deMyelination in mouse cortex
Nature Communications, 2020Co-Authors: Nicolas Snaidero, Bernard Zalc, Martin Kerschensteiner, Martina Schifferer, Aleksandra Mezydlo, Thomas MisgeldAbstract:Myelin, rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and Myelina-tion patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstructions, we report that in mouse cortex deMyelination as subtle as the loss of a single oligodendrocyte can trigger robust cell replacement and reMyelination timed by Myelin breakdown. This results in reliable rees-tablishment of the original Myelin pattern along continuously Myelinated axons, while in parallel, patchy isolated internodes emerge on previously unMyelinated axons. Therefore, in mammalian cortex, internodes along partially Myelinated cortical axons are typically not reestablished, suggesting that the cues that guide patchy Myelination are not preserved through cycles of de-and reMyelination. In contrast, Myelin sheaths forming continuous patterns show remarkable homeostatic resilience and reMyelinate with single axon precision.
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age related Myelin degradation burdens the clearance function of microglia during aging
Nature Neuroscience, 2016Co-Authors: Shima Safaiyan, Nicolas Snaidero, Nirmal Kannaiyan, Simone Brioschi, Knut Biber, Simon Yona, Aimee L Edinger, Steffen Jung, Moritz J RossnerAbstract:Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We found that Myelin pieces were gradually released from aging Myelin sheaths and were subsequently cleared by microglia. Myelin fragmentation increased with age and led to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related Myelin fragmentation is substantial, leading to lysosomal storage and contributing to microglial senescence and immune dysfunction in aging.
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Myelin membrane wrapping of cns axons by pi 3 4 5 p3 dependent polarized growth at the inner tongue
Cell, 2014Co-Authors: Nicolas Snaidero, Wiebke Mobius, Tim Czopka, Liesbeth H P Hekking, Cliff Mathisen, Dick Verkleij, Sandra Goebbels, Julia M Edgar, Doron MerklerAbstract:Central nervous system Myelin is a multilayered membrane sheath generated by oligodendrocytes for rapid impulse propagation. However, the underlying mechanisms of Myelin wrapping have remained unclear. Using an integrative approach of live imaging, electron microscopy, and genetics, we show that new Myelin membranes are incorporated adjacent to the axon at the innermost tongue. Simultaneously, newly formed layers extend laterally, ultimately leading to the formation of a set of closely apposed paranodal loops. An elaborated system of cytoplasmic channels within the growing Myelin sheath enables membrane trafficking to the leading edge. Most of these channels close with ongoing development but can be reopened in adults by experimentally raising phosphatidylinositol-(3,4,5)-triphosphate levels, which reinitiates Myelin growth. Our model can explain assembly of Myelin as a multilayered structure, abnormal Myelin outfoldings in neurological disease, and plasticity of Myelin biogenesis observed in adult life.
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Myelin membrane assembly is driven by a phase transition of Myelin basic proteins into a cohesive protein meshwork
PLOS Biology, 2013Co-Authors: Shweta Aggarwal, Nicolas Snaidero, Marie-theres Weil, Gesa Pahler, Steffen Frey, Paula Sanchez, Markus Zweckstetter, Andreas Janshoff, Anja Schneider, Iwan A T SchaapAbstract:Rapid conduction of nerve impulses requires coating of axons by Myelin. To function as an electrical insulator, Myelin is generated as a tightly packed, lipid-rich multilayered membrane sheath. Knowledge about the mechanisms that govern Myelin membrane biogenesis is required to understand Myelin disassembly as it occurs in diseases such as multiple sclerosis. Here, we show that Myelin basic protein drives Myelin biogenesis using weak forces arising from its inherent capacity to phase separate. The association of Myelin basic protein molecules to the inner leaflet of the membrane bilayer induces a phase transition into a cohesive mesh-like protein network. The formation of this protein network shares features with amyloid fibril formation. The process is driven by phenylalanine-mediated hydrophobic and amyloid-like interactions that provide the molecular basis for protein extrusion and Myelin membrane zippering. These findings uncover a physicochemical mechanism of how a cytosolic protein regulates the morphology of a complex membrane architecture. These results provide a key mechanism in Myelin membrane biogenesis with implications for disabling deMyelinating diseases of the central nervous system.
Richard H Quarles - One of the best experts on this subject based on the ideXlab platform.
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Comparison of CNS and PNS Myelin proteins in the pathology of Myelin disorders.
Journal of the neurological sciences, 2004Co-Authors: Richard H QuarlesAbstract:This brief overview summarizes some of the ways that the structure, location and function of proteins in Myelin sheaths affect the pathological abnormalities brought on by immunological, viral, genetic or other insults occurring in Myelin disorders. The composition of compact Myelin membranes is novel in comparison to other biological membranes, because of its high lipid content and the presence of several major proteins that are relatively specific for Myelin [1,2]. The overall morphological structures of compact central nervous system (CNS) and peripheral nervous system (PNS) Myelin are similar, even though they are formed by different cell types, that is, oligodendrocytes and Schwann cells, respectively. On the other hand, there are morphological differences in their periodicity and relationship to the Myelin-forming glial cells, quantitative differences in lipid composition, and important qualitative differences in protein composition. These differences in protein composition are likely to be especially important for determining the pathologies that characterize disorders of Myelin formation and degeneration in the CNS and PNS. Proteolipid protein (PLP) is a very hydrophobic tetraspan protein that accounts for over half the total protein in CNS Myelin [1,3], whereas the amount of PLP in the PNS is minimal. By contrast, the type 1 transmembrane P0 glycoprotein accounts for over half the protein in PNS Myelin [1,4,5]. Compact PNS Myelin also contains a 22kDa tetraspan glycoprotein, peripheral Myelin protein-22 (PMP-22), which accounts for less than 5% of the total and is absent in CNS Myelin [1,4,6]. Myelin basic protein (MBP) is a prominent, positively charged, extrinsic membrane protein of both CNS and PNS Myelin, which accounts for about 30% of the total in CNS Myelin, but only 5–15%
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Glycoproteins of Myelin sheaths
Journal of Molecular Neuroscience, 1997Co-Authors: Richard H QuarlesAbstract:A growing number of glycoproteins have been identified and characterized in Myelin and Myelin-forming cells. In addition to the major P0 glycoprotein of compact PNS Myelin and the Myelin-associated glycoprotein (MAG) in the periaxonal membranes of Myelin-forming oligodendrocytes and Schwann cells, the list now includes peripheral Myelin protein-22 (PMP-22), a 170 kDa glycoprotein associated with PNS Myelin and Schwann cells (P170k/SAG), Schwann cell Myelin protein (SMP), Myelin/oligodendrocyte glycoprotein (MOG), and oligodendrocyteMyelin glycoprotein (OMgp). Many of these glycoproteins are members of the immunoglobulin superfamily and express the adhesion-related HNK-1 carbohydrate epitope. This review summarizes recent findings concerning the structure and function of these glycoproteins of Myelin sheaths with emphasis on the physiological roles of oligosaccharide moieties.
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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, 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 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.
Ben A Barres - One of the best experts on this subject based on the ideXlab platform.
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schwann cells use tam receptor mediated phagocytosis in addition to autophagy to clear Myelin in a mouse model of nerve injury
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Amanda Brosius Lutz, Wonsuk Chung, Steven A Sloan, Glenn A Carson, Lu Zhou, Emilie Lovelett, Sean Posada, Bradley J Zuchero, Ben A BarresAbstract:Ineffective Myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of Myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS Myelin clearance are incompletely understood. We set out to discover new pathways of PNS Myelin clearance to identify novel strategies for activating Myelin clearance in the injured central nervous system, where Myelin debris is not cleared efficiently. Here we show that Schwann cells, the Myelinating glia of the PNS, collaborate with hematogenous macrophages to clear Myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired Myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in Myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated Myelin clearance, to the repertoire of cellular machinery used to clear Myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating Myelin clearance after CNS injury.
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the lipid sulfatide is a novel Myelin associated inhibitor of cns axon outgrowth
The Journal of Neuroscience, 2011Co-Authors: Alissa Winzeler, Wim Mandemakers, Melissa Stafford, Carolyn T Phillips, Ben A BarresAbstract:CNS Myelin is strongly inhibitory to growing axons and is thought to be a major contributor to CNS axon regenerative failure. Although a number of proteins present in Myelin, including Nogo, MAG, and oligodendrocyte-Myelin glycoprotein (OMgp), have been identified as Myelin-associated inhibitors, studies of mice lacking these genes suggest that additional inhibitors present in CNS Myelin remain to be identified. Here we have investigated the hypothesis that Myelin lipids contribute to CNS regenerative failure. We identified sulfatide, a major constituent of CNS Myelin, as a novel Myelin-associated inhibitor of neurite outgrowth. Sulfatide, but not galactocerebroside or ceramide, strongly inhibited the neurite outgrowth of retinal ganglion cells (RGCs) when used as a purified lipid substrate. The mechanism involved in sulfatide-mediated inhibition may share features with other known inhibitors, because the Rho inhibitor C3 transferase lessened these effects. Myelin in which sulfatide was lacking or blocked using specific antibodies was significantly less inhibitory to RGC neurite outgrowth in vitro than was wild-type Myelin, indicating that sulfatide is a major component of the inhibitory activity of CNS Myelin. Mice unable to make sulfatide did not regenerate RGC axons more robustly after optic nerve crush than wild-type littermates under normal conditions but did exhibit a small but significant enhancement in the extent of zymosan-induced regeneration. These results demonstrate that specific lipids can powerfully inhibit axon growth, identify sulfatide as a novel Myelin-associated axon growth inhibitor, and provide evidence that sulfatide inhibition contributes to axon regenerative failure in vivo .
B. D. Trapp - One of the best experts on this subject based on the ideXlab platform.
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Diseases Involving Myelin
Basic Neurochemistry, 2012Co-Authors: Susan M. Staugaitis, B. D. TrappAbstract:Publisher Summary This chapter focuses on multiple sclerosis and the acquired and inherited peripheral neuropathies. The integrity of Myelin sheaths is dependent upon the normal functioning of the Myelin-forming oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) as well as on the viability of the axons that they ensheath. Neuronal death inevitably leads to degeneration of axons and secondary degeneration of the Myelin surrounding them. Failure of synthesis of normal Myelin proteins or lipids is referred to as hypoMyelination or dysMyelination. Primary deMyelination involves the destruction of Myelin with relative sparing of axons, whereas secondary demyelination includes those disorders in which Myelin is involved only after damage to neurons and axons occurs. The integrity of Myelin sheaths is dependent upon the normal functioning of Myelin-forming oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) as well as on the viability of the axons that they ensheath.
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nmda receptors mediate calcium accumulation in Myelin during chemical ischaemia
Nature, 2006Co-Authors: Ileana Micu, B. D. Trapp, Qiubo Jiang, Elaine Coderre, Andrew Ridsdale, Liang Zhang, John Woulfe, Xinghua Yin, John E Mcrory, Renata RehakAbstract:Central nervous system Myelin is a specialized structure produced by oligodendrocytes that ensheaths axons, allowing rapid and efficient saltatory conduction of action potentials1. Many disorders promote damage to and eventual loss of the Myelin sheath, which often results in significant neurological morbidity. However, little is known about the fundamental mechanisms that initiate Myelin damage, with the assumption being that its fate follows that of the parent oligodendrocyte. Here we show that NMDA (N-methyl-d-aspartate) glutamate receptors mediate Ca2+ accumulation in central Myelin in response to chemical ischaemia in vitro. Using two-photon microscopy, we imaged fluorescence of the Ca2+ indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the Myelin sheath in adult rat optic nerves. The AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor antagonist NBQX2 completely blocked the ischaemic Ca2+ increase in oligodendroglial cell bodies, but only modestly reduced the Ca2+ increase in Myelin. In contrast, the Ca2+ increase in Myelin was abolished by broad-spectrum NMDA receptor antagonists (MK-801, 7-chlorokynurenic acid, d-AP53,4), but not by more selective blockers of NR2A and NR2B subunit-containing receptors (NVP-AAM0775 and ifenprodil2,4). In vitro ischaemia causes ultrastructural damage to both axon cylinders and Myelin6. NMDA receptor antagonism greatly reduced the damage to Myelin. NR1, NR2 and NR3 subunits were detected in Myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits are present for the formation of functional NMDA receptors. Our data show that the mature Myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate7,8,9, our finding that the Ca2+ increase was mediated in large part by activation of Myelinic NMDA receptors suggests a new mechanism of axo–Myelinic signalling. Such a mechanism may represent a potentially important therapeutic target in disorders in which deMyelination is a prominent feature, such as multiple sclerosis, neurotrauma, infections (for example, HIV encephalomyelopathy) and aspects of ischaemic brain injury.
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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, 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 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.
