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Current Neurology and Neuroscience... Jan 2007Guillain-Barré syndrome (GBS) is currently divided into the two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy... (Review)
Review
Guillain-Barré syndrome (GBS) is currently divided into the two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). This review highlights relevant recent publications, particularly on the pathophysiology of AMAN. Molecular mimicry of the bacterial lipo-oligosaccharide by the human gangliosides is now considered an important cause of AMAN. Gangliosides GM1, GM1b, GD1a, and GalNAc-GD1a expressed on the motor axolemma are likely to be the epitopes for antibodies in AMAN. At the nodes or paranodes, deposition of antiganglioside antibodies initially cause reversible conduction block followed by axonal degeneration. Electrodiagnostic findings support this process. Disruption of glycolipids, which are important to maintain ion channel clustering at the nodes and paranode, may impair nerve conduction. Genetic polymorphisms of Campylobacter jejuni determine the expression of the gangliosides on the bacterial wall. In contrast, target molecules in AIDP have not yet been identified. Meta-analyses show efficacy of plasmapheresis and immunoglobulin therapy, but not corticosteroids, in hastening recovery.
Topics: Guillain-Barre Syndrome; Humans
PubMed: 17217855
DOI: 10.1007/s11910-007-0022-6 -
Progress in Molecular Biology and... 2018Gangliosides are a family of sialic acid-containing glycosphingolipids highly expressed in the nervous system of vertebrates. Over the last 25years, research has... (Review)
Review
Gangliosides are a family of sialic acid-containing glycosphingolipids highly expressed in the nervous system of vertebrates. Over the last 25years, research has unmasked several of their neurobiological functions but the role of gangliosides in the nervous system remains not fully elucidated. Genetic disruption of genes for key enzymes involved in ganglioside biosynthesis led to the discovery of their diverse functions and highlighted the exquisite structural specificity required in this processes. In the nervous system, gangliosides regulate axonal caliber and organize ion channels at the nodes of Ranvier, a critical step to ensure fast conduction velocity of myelinated fibers. They also act as receptors for lectins located on apposing myelin membranes critical to maintain axon-glia interactions that result in cytoskeleton stabilization. After a lesion, gangliosides acting as receptors for glial-derived molecules present in the extracellular milieu can halt axon regeneration. Similarly, antiganglioside antibodies present in autoimmune neurological conditions can mimic this inhibitory effect on nerve repair. Studying the molecular details of the molecular interaction of gangliosides in trans with ligands present on apposing cell membranes and receptor/transducer molecules in cis interaction at the axolemma membrane, together with their downstream signaling pathways, represent a unique opportunity to expand our knowledge about the role of gangliosides in the nervous system.
Topics: Animals; Axons; Gangliosides; Humans; Regeneration; Signal Transduction
PubMed: 29747821
DOI: 10.1016/bs.pmbts.2018.03.001 -
PeerJ 2018Axonal stimulation with electric currents is an effective method for controlling neural activity. An electric field parallel to the axon is widely accepted as the...
Axonal stimulation with electric currents is an effective method for controlling neural activity. An electric field parallel to the axon is widely accepted as the predominant component in the activation of an axon. However, recent studies indicate that the transverse component to the axolemma is also effective in depolarizing the axon. To quantitatively investigate the amount of axolemma polarization induced by a transverse electric field, we computed the transmembrane potential () for a conductive body that represents an unmyelinated axon (or the bare axon between the myelin sheath in a myelinated axon). We also computed the transmembrane potential of the sheath-covered axonal segment in a myelinated axon. We then systematically analyzed the biophysical factors that affect axonal polarization under transverse electric stimulation for both the bare and sheath-covered axons. Geometrical patterns of polarization of both axon types were dependent on field properties (magnitude and field orientation to the axon). Polarization of both axons was also dependent on their axolemma radii and electrical conductivities. The myelin provided a significant "shielding effect" against the transverse electric fields, preventing excessive axolemma depolarization. Demyelination could allow for prominent axolemma depolarization in the transverse electric field, via a significant increase in myelin conductivity. This shifts the voltage drop of the myelin sheath to the axolemma. Pathological changes at a cellular level should be considered when electric fields are used for the treatment of demyelination diseases. The calculated term for membrane polarization () could be used to modify the current cable equation that describes axon excitation by an external electric field to account for the activating effects of both parallel and transverse fields surrounding the target axon.
PubMed: 30533309
DOI: 10.7717/peerj.6020 -
Neuron Aug 1994A direct role for neurons in CNS myelination has yet to be demonstrated. CNS myelination can be examined in cerebellar slice cultures, which faithfully reproduce both...
A direct role for neurons in CNS myelination has yet to be demonstrated. CNS myelination can be examined in cerebellar slice cultures, which faithfully reproduce both synthesis and wrapping of myelin. In an attempt to demonstrate a role for axolemma in this process, we generated more than 2000 axolemma-reactive monoclonal antibodies. One clone, G21.3, repeatedly blocked myelination in cerebellar slices, as documented by both biochemistry and morphology. The antibody caused a dramatic reduction in myelin lipid and protein synthesis. CNS white matter, sciatic nerve, and neuronal cultures were positively stained with G21.3, whereas oligodendrocytes and myelin were fully negative. The antibody identified a restricted number of proteins in purified axolemma. These results suggest a direct involvement of axons in CNS myelination.
Topics: Antibodies, Monoclonal; Antigens, Surface; Axons; Cells, Cultured; Central Nervous System; Cerebellum; Immunologic Techniques; In Vitro Techniques; Molecular Weight; Nerve Fibers, Myelinated; Nerve Tissue Proteins
PubMed: 8060622
DOI: 10.1016/0896-6273(94)90361-1 -
The Journal of Physiology Jul 2014The local anaesthetic lidocaine is known to block voltage-gated Na(+) channels (VGSCs), although at high concentration it was also reported to block other ion channel...
The local anaesthetic lidocaine is known to block voltage-gated Na(+) channels (VGSCs), although at high concentration it was also reported to block other ion channel currents as well as to alter lipid membranes. The aim of this study was to investigate whether the clinical regional anaesthetic action of lidocaine could be accounted for solely by the block of VGSCs or whether other mechanisms are also relevant. We tested the recovery of motor axon conduction and multiple measures of excitability by 'threshold-tracking' after ultrasound-guided distal median nerve regional anaesthesia in 13 healthy volunteers. Lidocaine caused rapid complete motor axon conduction block localized at the wrist. Within 3 h, the force of the abductor pollicis brevis muscle and median motor nerve conduction studies returned to normal. In contrast, the excitability of the motor axons at the wrist remained markedly impaired as indicated by a 7-fold shift of the stimulus-response curves to higher currents with partial recovery by 6 h and full recovery by 24 h. The strength-duration properties were abnormal with markedly increased rheobase and reduced strength-duration time constant. The changes in threshold during electrotonus, especially during depolarization, were markedly reduced. The recovery cycle showed increased refractoriness and reduced superexcitability. The excitability changes were only partly similar to those previously observed after poisoning with the VGSC blocker tetrodotoxin. Assuming an unaltered ion-channel gating, modelling indicated that, apart from up to a 4-fold reduction in the number of functioning VGSCs, lidocaine also caused a decrease of passive membrane resistance and an increase of capacitance. Our data suggest that the lidocaine effects, even at clinical 'sub-blocking' concentrations, could reflect, at least in part, a reversible structural impairment of the axolemma.
Topics: Adult; Anesthesia, Local; Anesthetics, Local; Axons; Cell Membrane; Female; Humans; Lidocaine; Male; Models, Neurological; Motor Neurons; Muscle, Skeletal; Neural Conduction; Voltage-Gated Sodium Channel Blockers
PubMed: 24710060
DOI: 10.1113/jphysiol.2014.270827 -
Neurochemical Research May 1981Axolemma-enriched fractions were isolated from the white matter of bovine corpus callosum via a purified preparation of myelinated axons which were osmotically shocked...
Axolemma-enriched fractions were isolated from the white matter of bovine corpus callosum via a purified preparation of myelinated axons which were osmotically shocked and fractionated on a discontinuous density gradient. Two membrane fractions of differing density were obtained: both were somewhat enriched over white matter whole homogenate in specific activity of acetylcholinesterase and 5'-nucleotidase and maximal binding capacity for saxitoxin. Both membrane fractions contained appreciable amounts of 2', 3'-cyclic nucleotide 3'-phosphohydrolase; the specific activity of antimycin-sensitive NAPH-cytochrome c reductase and cytochrome c oxidase indicated low levels of contamination by microsomal and mitochondrial membrane. The myelin which is concomitantly isolated with the axolemma-enriched fractions has a lipid and protein composition comparable to that of myelin isolated by other procedures. Both axolemma-enriched fractions contain about one half of their dry weight as lipid comprised of approximately 25% cholesterol, 25% galactolipid (cerebrosides and sulfatides in a molar ratio of about 4:1) and 50% phospholipid, mostly choline phosphatides and ethanolamine phospholes in an equimolar ratio. The axolemma fractions are also enriched in ganglioside content relative to the myelin fraction. The polypeptides of the axolemma-enriched fractions range from 20,000 to over 200,000 in molecular weight; the predominant proteins are in the range from 50,000 to 69,000. The most dense axolemma-enriched fraction is over fourfold enriched in glycoprotein content compared with myelin, with at least 10 different molecular-weight classes of glycoproteins as identified by Schiff stain of polyacrylamide gel protein profiles. The differences and similarities in the molecular composition of axolemma-enriched preparations which have been characterized to date are discussed.
Topics: Animals; Axons; Cattle; Cell Fractionation; Centrifugation, Density Gradient; Corpus Callosum; Glycoproteins; Lipids; Myelin Sheath; Nerve Tissue Proteins; Phospholipids
PubMed: 7279111
DOI: 10.1007/BF00964391 -
Journal of Neuroscience Research Feb 1994The amyloid precursor protein (APP) is widely distributed within the CNS, where it is expressed in both neurons and glia. We have isolated axolemma and...
The amyloid precursor protein (APP) is widely distributed within the CNS, where it is expressed in both neurons and glia. We have isolated axolemma and periaxolemmal-myelin from rat brain and have determined by Western blot that APPs, Mr 100-110 kDa, are major constituents of these membrane. Isolation of axolemma, periaxolemmal-myelin, and compact myelin show that while APP represents 1 and 0.6% of the proteins of these respective membranes, it is absent from compact myelin. These results indicate that APP transported down the axon is deposited at sites in the axolemma as well as the synapse, and that within the myelin complex, APP is targeted to the periaxolemmal domain. Both axolemma and periaxolemmal-myelin contained a 10.5 kDa APP peptide which, based on reactivity with anti-C-terminal APP antibodies but not with anti-N-terminal antibody, appears to be a membrane-associated C-terminal fragment. Western blots with antibodies to Alzheimer precursor-like proteins (APLP) indicate that APP immune reactivity is not a result of cross reactivity with APLPs. Isolation of axolemma from human autopsy material showed nearly identical results with a clear enrichment, relative to homogenate, of APP Mr 100-110 and the 10.5 kDa C-terminal peptide. The demonstration of APP in axolemma and periaxolemmal-myelin was replicated in membrane isolated from bovine brain. Bovine studies were extended to analysis of white matter clathrin-coated vesicles; these data show that coated vesicles isolated from white matter, under conditions that previous studies indicate are largely endocytic vesicles, contain levels of APP comparable to that found in axolemma and periaxolemmal-myelin. In addition, these vesicles contain cysteinyl and aspartyl proteases. Incubation of axolemma with cathepsin B at pH 6.0 caused a rapid loss in the immune reactivity of APP Mr 100-110 and Mr 10.5 when analyzed with antibodies to APP672-695. This appears to be the result of hydrolysis within the epitope and not proteolysis of APP or the C-terminal peptide, since no loss of reactivity was observed when analyzed with antibodies to sites more distal to the C-terminus. Thus, cathepsin B hydrolyses membrane bound APP close to the C-terminus and may be a useful tool for altering C-terminal APP function.
Topics: Amino Acid Sequence; Amyloid beta-Protein Precursor; Animals; Axons; Blotting, Western; Brain Chemistry; Brain Stem; Cathepsin B; Cathepsin D; Cattle; Cell Membrane; Clathrin; Electrophoresis, Polyacrylamide Gel; Humans; Hydrolysis; Microtubule-Associated Proteins; Molecular Sequence Data; Myelin Sheath; Neprilysin; Rats; Synaptic Vesicles
PubMed: 8176757
DOI: 10.1002/jnr.490370307 -
Current Opinion in Neurology Oct 1996Identification of new antigens in different patterns of Guillain-Barré syndrome has led to new pathophysiological concepts of Guillain-Barré syndrome and the related... (Review)
Review
Identification of new antigens in different patterns of Guillain-Barré syndrome has led to new pathophysiological concepts of Guillain-Barré syndrome and the related Miller-Fisher syndrome. Patients with Guillain-Barré syndrome occurring after Campylobacter jejuni infection have been found to develop more frequently axonal and motor forms of the syndrome. Anti-GM1 antibodies decreased Na+ current in the presence of complement. In acute axonal Guillain-Barré syndrome, macrophages were found in the periaxonal space without damaging myelin sheath. Important epitopes may be localized on the axolemma, but further studies are needed to confirm these observations.
Topics: Animals; Antibodies; Axons; Campylobacter Infections; Epitopes; HLA Antigens; Humans; Polyradiculoneuropathy; T-Lymphocytes
PubMed: 8894406
DOI: 10.1097/00019052-199610000-00002 -
Current Opinion in Neurobiology Dec 2013Nodes of Ranvier are specialized axonal domains formed in response to a glial signal. Recent research advances have revealed that both CNS and PNS nodes form by several... (Review)
Review
Nodes of Ranvier are specialized axonal domains formed in response to a glial signal. Recent research advances have revealed that both CNS and PNS nodes form by several overlapping molecular mechanisms. However, the precise nature of these mechanisms and the hierarchy existing between them is considerably different in CNS versus PNS nodes. Namely, the Schwann cells of the PNS, which directly contact the nodal axolemma, secrete proteins that cluster axonodal components at the edges of the growing myelin segment. In contrast, the formation of CNS nodes, which are not contacted by the myelinating glia, is surprisingly similar to the assembly of the axon initial segment and depends largely on axonal diffusion barriers.
Topics: Animals; Humans; Neurogenesis; Neuroglia; Neurons; Ranvier's Nodes
PubMed: 23831261
DOI: 10.1016/j.conb.2013.06.003 -
Journal of Clinical Immunology Jul 2014Multifocal motor neuropathy affects myelinated motor axons in limb nerves at multifocal sites. It is characterized by weakness and muscle atrophy, motor conduction... (Review)
Review
Multifocal motor neuropathy affects myelinated motor axons in limb nerves at multifocal sites. It is characterized by weakness and muscle atrophy, motor conduction block, and antibodies against ganglioside GM1 which is expressed on the axolemma of nodes of Ranvier and perinodal Schwann cells. Treatment by regular IVIg courses results in temporary improvement but cannot prevent slowly progressing weakness due to axonal degeneration. This review discusses possible mechanisms of conduction block and the reasons why motor axons are selectively affected in this disorder.
Topics: Animals; Autoantibodies; Axons; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Immunotherapy; Motor Neurons; Neural Conduction; Polyneuropathies; Ranvier's Nodes; Treatment Outcome
PubMed: 24801202
DOI: 10.1007/s10875-014-0023-6