Morphological progression of myelin abnormalities in IgM-monoclonal gammopathy of undetermined significance anti-myelin-associated glycoprotein neuropathy

To characterize the morphological progression of neuropathy associated with immunoglobulin M-monoclonal gammopathy of undetermined significance with anti-myelin-associated glycoprotein antibody, we assessed histopathologic features of sural nerve specimens from 15 patients, emphasizing widely spaced myelin (WSM), demyelination, and tomaculous changes. The frequency of WSM correlated with that of demyelination and tomaculous appearance in teased-fiber preparations. In longitudinal sections at nodes of Ranvier and paranodal regions, the spaces between terminal myelin loops, particularly those adjacent to the node of Ranvier, were widened, indicating an early change before demyelination, and there was concomitant swelling of terminal myelin loops. Some conspicuously swollen terminal myelin loops were detached from the paranodal axolemma, thereby widening the nodes of Ranvier. Tomacula coexisted frequently with redundant myelin loops and WSM, particularly in the outermost layer of myelin sheaths, suggesting that loosening of the outer layers contributes to their formation. By immunofluorescence microscopy, immunoglobulin M and myelin-associated glycoprotein were colocalized in paranodal regions and Schmidt-Lanterman incisures. Confocal analysis revealed colocalization of immunoglobulin M and complement product C3d corresponding to the area of WSM. Thus, morphological changes in terminal myelin loops, formation of WSM at paranodes, and subsequent dissociation from paranodal axolemma (which may be associated with activation of the complement pathway) likely contribute to demyelination in this condition. Loosening of compact myelin seems to contribute to tomacula formation.     

Remyelination following viral-induced demyelination: ferric ion-ferrocyanide staining of nodes of Ranvier within the CNS

Ferric ion-ferrocyanide (Fe-FeCN) staining was used to stain nodes of Ranvier in remyelinating central nervous system (CNS) axons following viral-induced demyelination. As at normal nodes, Fe-FeCN staining was observed on the cytoplasmic surface of the nodal axolemma of remyelinated fibers. These fibers were identified on the basis of inappropriately short internode lengths and thin myelin sheaths. Thus, newly formed nodes along remyelinated CNS axons recapitulate at least one normal nodal membrane property.     

Early onset of degenerative changes at nodes of Ranvier in alpha-motor axons of Cntf null (-/-) mutant mice

The nodes of Ranvier are sites of specific interaction between Schwann cells and axons. Besides their crucial role in transmission of action potentials, the nodes of Ranvier and in particular the paranodal axon-Schwann cell networks (ASNs) are thought to function as local centers in large motor axons for removal, degradation, and disposal of organelles. In order to test whether ciliary neurotrophic factor (CNTF), which is present at high levels in the Schwann cell cytoplasm, is involved in the maintenance of these structures, we have examined lumbar ventral root nerve fibers of alpha-motor neurons by electron microscopy in 3- and 9-month-old Cntf null ((-/-)) mutant mice. Nerve fibers and nodes of Ranvier in 3-month-old Cntf(-/-) mutants appeared morphologically normal, except that ASNs were more voluminous in the mutants than in wild-type control animals at this age. In 9-month-old Cntf(-/-) animals, morphological changes, such as reduction in nerve fiber and axon diameter, myelin sheath disruption, and loss of ASNs at nodes of Ranvier, were observed. These findings suggest that endogenous CNTF, in addition to its role in promoting motor neuron survival and regeneration, is needed for long-term maintenance of alpha-motor nerve fibers. The premature loss of paranodal ASNs in animals lacking CNTF, which seems to be a defect related to a disturbed interaction in the nodal region between the axon and its myelinating Schwann cells, could impede the maintenance of a normal milieu in the motor axon, preceding more general neuronal damage.     

Nodes of Ranvier in health and disease

Action potential propagation along myelinated axons depends on the geometry of the myelin unit and the division of the underlying axon to specialized domains. The latter include the nodes of Ranvier (NOR), the paranodal junction (PNJ) flanking the nodes, and the adjacent juxtaparanodal region that is located below the compact myelin of the internode. Each of these domains contains a unique composition of axoglial adhesion molecules (CAMs) and cytoskeletal scaffolding proteins, which together direct the placement of specific ion channels at the nodal and juxtaparanodal axolemma. In the last decade it has become increasingly clear that antibodies to some of these axoglial CAMs cause immune-mediated neuropathies. In the current review we detail the molecular composition of the NOR and adjacent membrane domains, describe the function of different CAM complexes that mediate axon-glia interactions along the myelin unit, and discuss their involvement and the underlying mechanisms taking place in peripheral nerve pathologies. This growing group of pathologies represent a new type of neuropathies termed “nodopathies” or “paranodopathies” that are characterized by unique clinical and molecular features which together reflect the mechanisms underlying the molecular assembly and maintenance of this specialized membrane domain.     

Effects of IDPN-induced axonal swellings on conduction in motor nerve fibers

Paranodal demyelination produces a reduction of conduction velocity and conduction block. The relative proportions of these changes appear to vary among different demyelinating disorders. In this study we have examined the effects on conduction of paranodal demyelination produced by giant axonal swellings. The axonal swellings were induced in rats by administration of beta, beta'-iminodipropionitrile (IDPN). In this experimental model synchronous axonal swellings occur in the proximal region of virtually every alpha-motorneuron without evidence of segmental demyelination or fiber loss. Conduction across the motor neuron was evaluated by two methods: a monosynaptic reflex pathway and intracellular recording from single motor neurons. Increases in the delay across the central region of the monosynaptic reflex pathway began between 2 and 4 days after toxin administration. Intracellular studies confirmed that the slowing occurred across the proximal regions of the motor axons; more distal regions of the motor axons were unaffected. The substantial reduction in conduction velocity over the swollen segment occurs with only moderate evidence of conduction block, as assayed by a reduction in the H-reflex/M-response amplitude ratio. Parallel morphological studies showed that in the enlarged fibers the myelin terminal loops maintained contact with the axon but were displaced from the paranodal region into the internode. The appearance of this "passive" paranodal demyelination correlated closely with the increase in conduction delay. We suggest that the contact maintained by the displaced myelin terminal loops with the axolemma allows saltatory conduction to continue, and explains the paucity of conduction block in this model despite the prominent conduction slowing.     

Schwann cell proliferation and migration during paranodal demyelination

This study examined Schwann cell behavior during paranodal demyelination induced by beta,beta'-iminodipropionitrile (IDPN). The stimuli for Schwann cell proliferation, extensively studied in vitro, are less well understood in vivo. Most in vivo systems previously used to examine Schwann cell proliferation in disease are dominated by loss of internodal myelin sheaths. As used in this study, IDPN administration produces neurofilamentous axonal swellings and paranodal demyelination, without segmental demyelination or fiber degeneration. We asked whether Schwann cells would proliferate following the restricted paranodal demyelination that accompanies the axonal swellings, and if so what the sources and distributions of new Schwann cells might be. IDPN was given as a single large dose (2 ml/kg) to 21-d-old rats. Neurofilamentous axonal swellings formed in the proximal regions of motor axons, reaching their greatest enlargement in the root exit zone 8 d after IDPN administration. These swellings subsequently migrated distally down the nerves at rates approaching 1 mm/d. The axonal enlargement was consistently associated with displacement of the myelin sheath attachment sites into internodal regions, and consequent paranodal demyelination. This stage was associated with perikaryal changes, including nucleolar enlargement, "girdling" of the perikaryon, and formation of attenuated stalks separating the perinuclear region from the external cytoplasmic collar. Schwann cells proliferated abundantly during this stage. Daughter Schwann cells migrated within the endoneurial space (outside the nerve fiber basal laminae) to overlie the demyelinated paranodes of swollen nerve fibers. In these regions, local proliferation of Schwann cells continued, resulting in large paranodal clusters of Schwann cells. As the axonal calibers subsequently returned to normal, the outermost myelin lamellae of the original internodes returned to their paranodal attachment sites and the supernumerary Schwann cells disappeared. Formation of short internodes, segmental demyelination, and nerve fiber loss were rare phenomena. These results indicate that paranodal demyelination is a sufficient stimulus to excite abundant Schwann cell proliferation; neither internodal demyelination nor myelin breakdown is a necessary stimulus for mitosis. The 3H-thymidine incorporation studies indicated that the sources of new Schwann cells included markedly increased division of the Schwann cells of unmyelinated fibers and, as they formed, supernumerary Schwann cells. In addition, there were rare examples of 3H-thymidine incorporation by Schwann cells associated with myelinated nerve fibers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Rapid alterations of the axon membrane in antibody-mediated demyelination

Alterations of nodal and paranodal axolemma of the rat sciatic nerve were investigated in antigalactocerebroside serum-induced demyelination. A ferric ion-ferrocyanide (FeFCN) stain that appears to stain the regions with a high sodium channel density in nerve fibers was applied. When acute conduction block was initiated 20 to 180 minutes after the antiserum injection, myelin terminal loops began to be detached from the paranodal axolemma and reaction product of FeFCN stain originally localized at the nodes decreased in density and extended to the paranodal axolemma. By the time that complete conduction block was established, 5 hours after the injection, FeFCN stain was barely detectable around the nodal area. The loss of staining was associated with detachment and vesiculovacuolar degeneration of the paranodal myelin. This rapid deterioration and disappearance of normal cytochemical characteristics of the axolemma in the presence of only modest paranodal demyelination could be a morphological correlate of the loss of excitability of the axon membrane.     

ATYPICAL AXON-SCHWANN CELL RELATIONSHIPS IN THE COMMON PERONEAL NERVE OF THE DYSTROPHIC MOUSE: AN ULTRASTRUCTURAL STUDY

Abstracts Jaros E. & Bradley W.G. (1979) Neuropathology and Applied Neurobiology 5, 133–147
Atypical axon-Schwann cell relationships in the common peroneal nerve of the dystrophic mouse: an ultrastructural study
Several atypical features of myelination of the peripheral nervous system are reported in common peroneal nerve of dystrophic mice (129 Re J dy/dy): ( i ) central nervous system-like contact between myelin sheaths of adjacent nerve fibres; ( ii ) nodes and internodes of myelinated fibres enwrapped with cytoplasmic processes of Schwann cells from adjacent nerve fibres; ( iii ) Schwann cells of adjacent nerve fibres co-operating in formation of a single myelin sheath; and ( iv ) a single Schwann cell myelinating two separate axons. In view of the presence of similar features of myelination in the central nervous system, where the myelin producing cells lack basement membrane, we suggest that in the dystrophic peripheral nerves the development of these features can be attributed to the partial deficiency of the Schwann cell basement membrane. Two types of widened nodes of Ranvier are also identified: ( i ) nodes with paranodal damage; and ( ii ) nodes without paranodal damage. In addition, abnormal features of myelination are described which are likely to represent altered Schwann celliaxon relationships during demyelination and remyelination and/or decreased myelinating ability of Schwann cells. We interpret these findings as indicating a metabolic disorder of Schwann cells. They provide an experimental model for the investigation of factors involved in the origin and maintenance of the structural organization of peripheral nerve.     

Transfer of horseradish peroxidase from oligodendrocyte to axon in the myelinating neonatal rat optic nerve: Artefact or transcellular exchange?

In this paper we make the surprising observation that intracellular injection of horseradish peroxidase (HRP) into a single myelinating oligodendrocyte also resulted in localised HRP labelling at the nodes of Ranvier of some axons of the unit. It appeared that HRP had been transferred to the nodal axoplasm from the paranodal loops of the HRP-filled oligodendrocyte. Three HRP-filled oligodendrocytes from isolated optic nerves of 14-day-old rats were analysed by serial section electron microscopy, and HRP was observed in the axonal cytoplasm at three of the nodes of Ranvier delineated by one of the cells. At labelled nodes, HRP was of a uniform intensity throughout the nodal axoplasm. Axonal labelling gradually diminished along the paranodal regions and was not evident in the contiguous internodal axoplasm beyond 20 μm from the node. The myelin sheaths, paranodal loops, and axons appeared normal at labelled nodes, and the paranodal loops and astrocyte perinodal processes adjacent to those of the HRP-filled oligodendrocyte unit did not contain HRP. There was no evidence of extracellular HRP or tissue damage in the surrounding neuropil, and axons neighbouring those enwrapped by the HRP-filled oligodendrocyte did not contain HRP. The possibility that axonal labelling was an artefact of either iontophoretic injection or tissue preparation is discussed. This provocative finding is not definite proof of exchange, but the balance of evidence supports the possibility that there was transcellular exchange of HRP at paranodes between the labelled oligodendrocyte and some of the axons in the unit. The rarity of HRP transfer to axons suggests that it may be a transient or labile event. It is not clear whether oligodendrocyte to axon macromolecular exchange has real physiological and/or pathological significance. © Wiley-Liss, Inc.     

Nodes of Ranvier in skin biopsies of patients with diabetes mellitus

Paranodal demyelination has been discussed as a potential mechanism of nerve fiber damage in diabetic neuropathy (DNP). Studies on human tissue are limited, as nerve biopsies are invasive and only rarely performed in patients with confirmed DNP. Skin biopsy has recently been suggested as a tool to analyze paranodal and nodal changes of myelinated fibers. We analyzed the myelinated fibers of skin biopsies of 35 patients with DNP, 17 patients with diabetes mellitus (DM) without neuropathy, and 30 normal controls. Immunofluorescence of skin sections with antibodies against Caspr, neurofascin, sodium channels, and myelin basic protein was performed to assess paranodal/nodal architecture, segmental demyelination, and myelinated nerve fibers. Staining with antibodies against protein gene product 9.5 was used to quantify unmyelinated nerve fibers. There was an increase of elongated Ranvier nodes and a dispersion of neurofascin at the distal leg in patients with DM with and without neuropathy and at the finger in patients with DNP. An increased dispersion of Caspr was only found in biopsies of the finger in patients with DNP. Skin biopsy may be an appropriate tool to analyze nodes of Ranvier in patients with DM. Structural nodal changes are detectable in DNP and even in diabetic patients without neuropathy.     

Ultrastructural analysis of the paranodal junction of myelinated fibers in 31-month-old-rats

Recent studies have revealed a significant decrease in white matter volume, including loss of myelin, with age but minimal decrease in gray matter volume (Guttmann et al., [1998] Neurology 50:972-978). Myelin is necessary for the rapid conduction of impulses along axons. Myelinated nerve includes various domains, the node of Ranvier, the paranodal region, the juxtaparanodal region and the internode. The paranodal junction may serve to anchor the myelin sheath to the axon. We analyzed the ultrastructure of the paranodal region in myelinated fibers from the aged rat brain. Severe alterations of myelinated fibers were observed in 31-month-old rats, resulting in the appearance of macrophages, splitting of the myelin sheath, myelin balloon formation and separation from the axon. Many paranodal retractions of myelinated axons occurred in the aged rats. It should be noted that the paranodal junction is functionally important, serving to anchor the myelin to the axon and that there is a diffusion barrier in the paranodal region. We analyzed myelin-related proteins from young and aged rat brains. The 21.5-kDa isoform of myelin basic protein (MBP) almost disappeared in the 31-month-old rats, whereas other myelin proteins were not significantly changed between young and aged rats. These results suggest that this isoform, a highly cationic charged major dense component protein that binds lipid bilayer in the membrane, may participate in the formation of a paranodal diffusion barrier at the myelin/noncompact membrane border.     

COPPER BINDING AT PNS NODES OF RANVIER DURING DEMYELINATION AND REMYELINATION IN THE PERINEURIAL WINDOW

Nodes of Ranvier of peripheral nerves are associated with mucopolysaccharide which is capable of binding a wide variety of cations. The present study has determined the changes in the binding properties of the node of Ranvier during demyelination and remyelination in the perineurial window. The location of copper ion binding, visualized as a dense copper ferrocyanide precipitate, was studied in teased fibres from 60 rat peroneal nerves with single perineurial windows and from 8 normal nerves. In normal nerves, precipitate was present over the nodal axon and at the borders of the paranodal axon. Before demyelination, severely beaded fibres sited within the perineurial window displayed a reduction or a loss of nodal precipitate. During the period of myelin phagocytosis and demyelination, precipitate was absent throughout the denuded axon but present at adjacent, uninvolved nodes. At the commencement of remyelination, precipitate appeared at the newlycreated nodal and paranodal regions and at interfaces between preserved and remyelinating internodes. The density increased with myelin thickening. These findings indicate: (1) severely beaded regions lose their normal binding property before undergoing demyelination, (2) demyelinated regions do not bind copper ions, (3) remyelinating fibres bind copper ions at newly-created nodes and (4) Schwann cells are responsible for the production of nodal mucopolysaccharides.     

Induction of paranodal myelin detachment and sodium channel loss in vivo by Campylobacter jejuni DNA-binding protein from starved cells (C-Dps) in myelinated nerve fibers

In an axonal variant of Guillain–Barré syndrome (GBS) associated with Campylobacter jejuni (C. jejuni) enteritis, the mechanism underlying axonal damage is obscure. We purified and characterized a DNA-binding protein from starved cells derived from C. jejuni (C-Dps). This C-Dps protein has significant homology with Helicobacter pylori neutrophil-activating protein (HP-NAP), which is chemotactic for human neutrophils through binding to sulfatide. Because sulfatide is essential for paranodal junction formation and for the maintenance of ion channels on myelinated axons, we examined the in vivo effects of C-Dps. First, we found that C-Dps specifically binds to sulfatide by ELISA and immunostaining of thin-layer chromatograms loaded with various glycolipids. Double immunostaining of peripheral nerves exposed to C-Dps with anti-sulfatide antibody and anti-C-Dps antibody revealed co-localization of them. When C-Dps was injected into rat sciatic nerves, it densely bound to the outermost parts of the myelin sheath and nodes of Ranvier. Injection of C-Dps rapidly induced paranodal myelin detachment and axonal degeneration; this was not seen following injection of PBS or heat-denatured C-Dps. Electron microscopically, C-Dps-injected nerves showed vesiculation of the myelin sheath at the nodes of Ranvier. Nerve conduction studies disclosed a significant reduction in compound muscle action potential amplitudes in C-Dps-injected nerves compared with pre-injection values, but not in PBS-, heat-denatured C-Dps-, or BSA-injected nerves. However, C-Dps did not directly affect Na⁺ currents in dissociated hippocampal neurons. Finally, when C-Dps was intrathecally infused into rats, it was deposited in a scattered pattern in the cauda equina, especially in the outer part of the myelin sheath and the nodal region. In C-Dps-infused rats, but not in BSA-infused ones, a decrease in the number of sodium channels, vesiculation of the myelin sheath, axonal degeneration and infiltration of Iba-1-positive macrophages were observed. Thus, we consider that C-Dps damages myelinated nerve fibers, possibly through interference with paranodal sulfatide function, and may contribute to the axonal pathology seen in C. jejuni-related GBS.     

Demyelination of Sternarchus electrocyte fibers by injection of diphtheria toxin

Diphtheria toxin was injected into the electric organ of the gymnotid fish, Sternarchus albifrons. After 10 days, there was extensive demeylination of electrocyte fibers in the area of injection. Electron microscopy showed that paranodal loops of myelin do not separately cleanly from the axon, and remnants of the myelin loops may persist after demyelination of the internodes is nearly complete. The dense cytoplasmic undercoating of the nodal axolemma may disappear before the paranodal junctions are completely gone. Observations of demyelination of internodes between the elaborate, inexcitable nodes suggest that the presence of myelin may not be necessary for the maintenance of structural differentiation of this region of the axolemma. Use of diphtheria toxin to demyelinate Sternarchus electrocytes may provide a useful system for experimental neuropathological studies.     

Age-related molecular reorganization at the node of Ranvier

In myelinated axons, action potential conduction is dependent on the discrete clustering of ion channels at specialized regions of the axon, termed nodes of Ranvier. This organization is controlled, at least in part, by the adherence of myelin sheaths to the axolemma in the adjacent region of the paranode. Age-related disruption in the integrity of internodal myelin sheaths is well described and includes splitting of myelin sheaths, redundant myelin, and fluctuations in biochemical constituents of myelin. These changes have been proposed to contribute to age-related cognitive decline; in previous studies of monkeys, myelin changes correlate with cognitive performance. In the present study, we hypothesize that age-dependent myelin breakdown results in concomitant disruption at sites of axoglial contact, in particular at the paranode, and that this disruption alters the molecular organization in this region. In aged monkey and rat optic nerves, immunolabeling for voltage-dependent potassium channels of the Shaker family (Kv1.2), normally localizing in the adjacent juxtaparanode, were mislocalized to the paranode. Similarly, immunolabeling for the paranodal marker caspr reveals irregular caspr-labeled paranodal profiles, suggesting that there may be age-related changes in paranodal structure. Ultrastructural analysis of paranodal segments from optic nerve of aged monkeys shows that, in a subset of myelinated axons with thick sheaths, some paranodal loops fail to contact the axolemma. Thus, age-dependent myelin alterations affect axonal protein localization and may be detrimental to maintenance of axonal conduction.     

Dysregulation of axonal sodium channel isoforms after adult-onset chronic demyelination

Demyelination results in conduction block through changes in passive cable properties of an axon and in the expression and localization of axonal ion channels. We show here that adult-onset chronic demyelination, such as occurs in demyelinating disorders and after nerve injury, alters the complement of axonal voltage-dependent Na+ (Nav) channel isoforms and their localization. As a model, we used heterozygous transgenic mice with two extra copies of the proteolipid protein gene (Plp/-). Retinal ganglion cell axons in these mice myelinate normally, with young Plp/- and wild-type mice expressing Nav1.2 at low levels, whereas Nav1.6 is clustered in high densities at nodes of Ranvier. At 7 months of age, however, Plp/- mice exhibit severe demyelination and oligodendrocyte cell death, leading to a profound reduction in Nav1.6 clusters, loss of the paranodal axoglial apparatus, and a marked increase in Nav1.2. We conclude that myelin is crucial not only for node of Ranvier formation, but also to actively maintain the proper localization and complement of distinct axonal Nav channel isoforms throughout life. The altered Nav channel isoform localization and complement induced by demyelination may contribute to the pathophysiology of demyelinating disorders and nerve injury.     

Nodal sodium channel domain integrity depends on the conformation of the paranodal junction,not on the presence of transverse bands

Our understanding of the role that axoglial interactions play in node of Ranvier formation and maintenance remains incomplete. Previous studies of CNS myelinated fibers of CGT-null mice showed abnormalities in the arrangement of paranodal myelin loops and absence of a conspicuous component of the paranodal junction, the ridge-like intercellular transverse bands. Axolemmal sodium channel domains were largely preserved at nodes of Ranvier but displayed some abnormalities in form. Using a combination of freeze-fracture and immunocytochemical methods, we have found additional evidence documenting abnormalities in the size, shape, and location of axolemmal sodium channel clusters in CGT-null mice as well as evidence that these nodal abnormalities are complementary to the organization of paranodal myelin loops, despite the absence of transverse bands. We conclude that the differentiated form of the nodal axolemma and the distribution of axolemmal sodium channels depend on the conformation of paranodal axoglial contacts but not on the presence of transverse bands at the sites of contact.     

Differential expression of gangliosides on the surfaces of myelinated nerve fibers

The binding of cholera and tetanus toxins to receptors on the surfaces of teased nerve fibers was used to localize GM1 and G1b-series gangliosides, respectively, by immunocytochemical methods. Native fibers and fibers treated with various hydrolytic enzymes to degrade specific surface components were studied. With native fibers, both toxins bound abundantly to nodes of Ranvier and poorly to the most external, internodal Schwann cell surfaces. Treatment of the fibers with proteases, hyaluronidase, and chondroitin ABC lyase neither eliminated receptors at the nodes nor unmasked receptors over the internodes. The axolemma underlying the paranodal or internodal myelin, exposed by extensive treatment with protease, bound both toxins in large amounts. Neuraminidase action induced cholera toxin receptors on the Schwann cell surface; these receptors were insensitive to protease. The results indicate that GM1 and G1b-series gangliosides are predominantly localized to axonal and glial structures of the node of Ranvier and to paranodal/internodal Axolemma, and that polysialogangliosides not of the G1b-series are present on the internodal Schwann cell surface.     

The node of Ranvier in CNS pathology

Healthy nodes of Ranvier are crucial for action potential propagation along myelinated axons, both in the central and in the peripheral nervous system. Surprisingly, the node of Ranvier has often been neglected when describing CNS disorders, with most pathologies classified simply as being due to neuronal defects in the grey matter or due to oligodendrocyte damage in the white matter. However, recent studies have highlighted changes that occur in pathological conditions at the node of Ranvier, and at the associated paranodal and juxtaparanodal regions where neurons and myelinating glial cells interact. Lengthening of the node of Ranvier, failure of the electrically resistive seal between the myelin and the axon at the paranode, and retraction of myelin to expose voltage-gated K⁺ channels in the juxtaparanode, may contribute to altering the function of myelinated axons in a wide range of diseases, including stroke, spinal cord injury and multiple sclerosis. Here, we review the principles by which the node of Ranvier operates and its molecular structure, and thus explain how defects at the node and paranode contribute to neurological disorders.     

IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block

We studied a patient with amyotrophic lateral sclerosis, multifocal motor conduction block, and IgM anti-GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes, and in some instances, they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve, the serum IgM bound to the nodes of Ranvier, and the binding activity was removed by preincubation with GM1. These observations suggest that anti-GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve.