RESUMEN
The evolution of ion channel clustering at nodes of Ranvier enabled the development of complex vertebrate nervous systems. At mammalian nodes, the K+ leak channels TRAAK and TREK-1 underlie membrane repolarization. Despite the molecular similarities between nodes and the axon initial segment (AIS), TRAAK and TREK-1 are reportedly node-specific, suggesting a unique clustering mechanism. However, we show that TRAAK and TREK-1 are enriched at both nodes and AIS through a common mechanism. We identified a motif near the C-terminus of TRAAK that is necessary and sufficient for its clustering. The motif first evolved among cartilaginous fish. Using AnkyrinG (AnkG) conditional knockout mice, CRISPR/Cas9-mediated disruption of AnkG, co-immunoprecipitation, and surface recruitment assays, we show that TRAAK forms a complex with AnkG and that AnkG is necessary for TRAAK's AIS and nodal clustering. In contrast, TREK-1's clustering requires TRAAK. Our results expand the repertoire of AIS and nodal ion channel clustering mechanisms and emphasize AnkG's central role in assembling excitable domains.
Asunto(s)
Ancirinas , Axones , Ratones Noqueados , Canales de Potasio de Dominio Poro en Tándem , Animales , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genética , Axones/metabolismo , Ratones , Ancirinas/metabolismo , Ancirinas/genética , Nódulos de Ranvier/metabolismo , Humanos , Secuencias de Aminoácidos , Evolución MolecularRESUMEN
BACKGROUND: To investigate Ranvier's autoantibodies prevalence and isotypes in various peripheral neuropathy variants, compare clinical features between seronegative and seropositive patients, and elucidate immune mechanisms underlying antibody generation. METHODS: Antibodies against anti-neurofascin-155 (NF155), NF186, contactin-1 (CNTN1), CNTN2, contactin-associated protein 1 (CASPR1), and CASPR2 were identified through cell-based assays. Plasma cytokines were analyzed in anti-NF155 antibody-positive chronic inflammatory demyelinating polyneuropathy (NF155+ CIDP) and Ranvier's antibodies-negative CIDP (Ab- CIDP) patients using a multiplexed fluorescent immunoassay, validated in vitro in a cell culture model. RESULTS: In 368 plasma samples, 50 Ranvier's autoantibodies were found in 45 individuals, primarily in CIDP cases (25 out of 69 patients) and in 10 out of 122 Guillain-Barré syndrome patients. Anti-NF155 and CNTN1-IgG were exclusive to CIDP. Fourteen samples were NF155-IgG, primarily IgG4 subclass, linked to CIDP features including early onset, tremor, sensory disturbance, elevated CSF protein, prolonged motor latency, conduction block, and poor treatment response. NF155-IgG had low sensitivity (20.28%) but high specificity (100%) for CIDP, rising to 88.88% with tremor and prolonged motor latency. Cytokine profiling in NF155+ CIDP revealed distinct immune responses involving helper T cells, toll-like receptor pathways. Some NF155+ CIDP patients had circulating NF155-specific B cells producing NF155-IgG without antigen presence, suggesting therapeutic potential. CONCLUSION: The study emphasizes the high specificity and sensitivity of NF155-IgG for diagnosing CIDP characterized by distinctive features. Further investigation into circulating NF155-specific B cell phenotypes may pave the way for B cell directed therapy.
Asunto(s)
Autoanticuerpos , Moléculas de Adhesión Celular , Factores de Crecimiento Nervioso , Fenotipo , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Masculino , Femenino , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/inmunología , Factores de Crecimiento Nervioso/inmunología , Factores de Crecimiento Nervioso/sangre , Persona de Mediana Edad , Autoanticuerpos/sangre , Anciano , Adulto , Citocinas/sangre , Nódulos de Ranvier/inmunología , Contactina 1/inmunologíaRESUMEN
Myelinated axons conduct action potentials, or spikes, in a saltatory manner. Inward current caused by a spike occurring at one node of Ranvier spreads axially to the next node, which regenerates the spike when depolarized enough for voltage-gated sodium channels to activate, and so on. The rate at which this process progresses dictates the velocity at which the spike is conducted and depends on several factors including axial resistivity and axon diameter that directly affect axial current. Here we show through computational simulations in modified double-cable axon models that conduction velocity also depends on extracellular factors whose effects can be explained by their indirect influence on axial current. Specifically, we show that a conventional double-cable model, with its outside layer connected to ground, transmits less axial current than a model whose outside layer is less absorptive. A more resistive barrier exists when an axon is packed tightly between other myelinated fibers, for example. We show that realistically resistive boundary conditions can significantly increase the velocity and energy efficiency of spike propagation, while also protecting against propagation failure. Certain factors like myelin thickness may be less important than typically thought if extracellular conditions are more resistive than normally considered. We also show how realistically resistive boundary conditions affect ephaptic interactions. Overall, these results highlight the unappreciated importance of extracellular conditions for axon function.
Asunto(s)
Potenciales de Acción , Axones , Modelos Neurológicos , Fibras Nerviosas Mielínicas , Conducción Nerviosa , Potenciales de Acción/fisiología , Axones/fisiología , Animales , Fibras Nerviosas Mielínicas/fisiología , Conducción Nerviosa/fisiología , Nódulos de Ranvier/fisiología , Simulación por Computador , Humanos , Vaina de Mielina/fisiologíaRESUMEN
BACKGROUND: Homozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation presented with recurrent GBS. Here we determine the localization and possible role of membrane-bound complement regulators, including CD59, in the peripheral nervous systems (PNS) of mice and humans. METHODS: We examined the localization of membrane-bound complement regulators in the peripheral nerves of healthy humans and a CD59-deficient patient, as well as in wild-type (WT) and CD59a-deficient mice. Cross sections of teased sciatic nerves and myelinating dorsal root ganglia (DRG) neuron/Schwann cell cultures were examined by confocal and electron microscopy. RESULTS: We demonstrate that CD59a-deficient mice display normal peripheral nerve morphology but develop myelin abnormalities in older age. They normally express myelin protein zero (P0), ankyrin G (AnkG), Caspr, dystroglycan, and neurofascin. Immunolabeling of WT nerves using antibodies to CD59 and myelin basic protein (MBP), P0, and AnkG revealed that CD59 was localized along the internode but was absent from the nodes of Ranvier. CD59 was also detected in blood vessels within the nerve. Finally, we show that the nodes of Ranvier lack other complement-membrane regulatory proteins, including CD46, CD55, CD35, and CR1-related gene-y (Crry), rendering this area highly exposed to complement attack. CONCLUSION: The Nodes of Ranvier lack CD59 and are hence not protected from complement terminal attack. The myelin unit in human PNS is protected by CD59 and CD55, but not by CD46 or CD35. This renders the nodes and myelin in the PNS vulnerable to complement attack and demyelination in autoinflammatory Guillain-Barré syndrome, as seen in CD59 deficiency.
Asunto(s)
Síndrome de Guillain-Barré , Proteínas de la Membrana , Ratones , Humanos , Animales , Nódulos de Ranvier , Proteínas del Sistema Complemento , Antígenos CD59/genética , Antígenos CD55/genéticaRESUMEN
The Contactin-associated protein 1 (Cntnap1) mouse mutants fail to establish proper axonal domains in myelinated axons. Human CNTNAP1 mutations are linked to hypomyelinating neuropathy-3, which causes severe neurological deficits. To understand the human neuropathology and to model human CNTNAP1C323R and CNTNAP1R764C mutations, we generated Cntnap1C324R and Cntnap1R765C mouse mutants, respectively. Both Cntnap1 mutants show weight loss, reduced nerve conduction, and progressive motor dysfunction. The paranodal ultrastructure shows everted myelin loops and the absence of axo-glial junctions. Biochemical analysis reveals that these Cntnap1 mutant proteins are nearly undetectable in the paranodes, have reduced surface expression and stability, and are retained in the neuronal soma. Postnatal transgenic expression of Cntnap1 in the mutant backgrounds rescues the phenotypes and restores the organization of axonal domains with improved motor function. This study uncovers the mechanistic impact of two human CNTNAP1 mutations in a mouse model and provides proof of concept for gene therapy for CNTNAP1 patients.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Vaina de Mielina , Humanos , Ratones , Animales , Vaina de Mielina/metabolismo , Axones/metabolismo , Enfermedad de Charcot-Marie-Tooth/genética , Neuroglía/patología , Modelos Animales de Enfermedad , Nódulos de Ranvier/metabolismo , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismoRESUMEN
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is recognized as a syndrome caused by multiple pathologies. Since the 2010s, it has been clarified that autoantibodies against membranous proteins localized in the nodes of Ranvier and paranodes are positive in subsets of CIDP patients, leading to proposing a new disease concept called autoimmune nodopathies, which is independent of CIDP, in the revised international CIDP guidelines. This article reviews the significance of these autoantibodies, especially anti-neurofascin 155 and anti-contactin 1 antibodies, which have been the most prevalent and achieved a higher degree of consensus.
Asunto(s)
Moléculas de Adhesión Celular , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Nódulos de Ranvier/metabolismo , Nódulos de Ranvier/patología , Autoanticuerpos/metabolismo , Factores de Crecimiento NerviosoRESUMEN
Major depressive disorder (MDD) and chronic unpredictable stress (CUS) in animals feature comparable cellular and molecular disturbances that involve neurons and glial cells in gray and white matter (WM) in prefrontal brain areas. These same areas demonstrate disturbed connectivity with other brain regions in MDD and stress-related disorders. Functional connectivity ultimately depends on signal propagation along WM myelinated axons, and thus on the integrity of nodes of Ranvier (NRs) and their environment. Various glia-derived proteoglycans interact with NR axonal proteins to sustain NR function. It is unclear whether NR length and the content of associated proteoglycans is altered in prefrontal cortex (PFC) WM of human subjects with MDD and in experimentally stressed animals. The length of WM NRs in histological sections from the PFC of 10 controls and 10 MDD subjects, and from the PFC of control and CUS rats was measured. In addition, in WM of the same brain region, five proteoglycans, tenascin-R and NR protein neurofascin were immunostained or their levels measured with western blots. Analysis of covariance and t-tests were used for group comparisons. There was dramatic reduction of NR length in PFC WM in both MDD and CUS rats. Proteoglycan BRAL1 immunostaining was reduced at NRs and in overall WM of MDD subjects, as was versican in overall WM. Phosphacan immunostaining and levels were increased in both in MDD and CUS. Neurofascin immunostaining at NRs and in overall WM was significantly increased in MDD. Reduced length of NRs and increased phosphacan and neurocan in MDD and stressed animals suggest that morphological and proteoglycan changes at NRs in depression may be related to stress exposure and contribute to connectivity alterations. However, differences between MDD and CUS for some NR related markers may point to other mechanisms affecting the structure and function of NRs in MDD.
Asunto(s)
Trastorno Depresivo Mayor , Sustancia Blanca , Humanos , Ratas , Animales , Sustancia Blanca/patología , Nódulos de Ranvier/metabolismo , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo , Corteza Prefrontal/metabolismo , Versicanos/metabolismoRESUMEN
The action potential conduction along the axon is highly dependent on the healthy interactions between the axon and myelin-producing glial cells. Myelin, which facilitates action potential, is the protective insulation around the axon formed by Schwann cells and oligodendrocytes in the peripheral (PNS) and central nervous system (CNS), respectively. Myelin is a continuous structure with intermittent gaps called nodes of Ranvier, which are the sites enriched with ion channels, transmembrane, scaffolding, and cytoskeletal proteins. Decades-long extensive research has identified a comprehensive proteome with strictly regularized localization at the node of Ranvier. Concurrently, axon-glia interactions at the node of Ranvier have gathered significant attention as the pathophysiological targets for various neurodegenerative disorders. Numerous studies have shown the alterations in the axon-glia interactions culminating in neurological diseases. In this review, we have provided an update on the molecular composition of the node of Ranvier. Further, we have discussed in detail the consequences of disruption of axon-glia interactions during the pathogenesis of various CNS and PNS disorders.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico , Nódulos de Ranvier , Humanos , Nódulos de Ranvier/metabolismo , Nódulos de Ranvier/patología , Neuroglía/metabolismo , Vaina de Mielina/patología , Vaina de Mielina/fisiología , Axones/metabolismoRESUMEN
Large-diameter myelinated fibers in sciatic nerves are composed of both Aα/ß-afferent fibers and Aα-efferent fibers to convey sensory and motor impulses, respectively, via saltatory conduction for rapid leg responses. Saltatory conduction and electrophysiological properties at the nodes of Ranvier (NRs) of these sciatic nerve fibers have not been directly studied. We used ex vivo sciatic nerve preparations from rats and applied patch-clamp recordings at the NRs of both Aα/ß-afferent fibers and Aα-efferent fibers in the sciatic nerves to characterize their saltatory conduction and intrinsic electrophysiological properties. The velocity and frequency of saltatory conduction in both types of fibers were similar. Resting membrane potentials (RMPs), input resistance, action potential (AP) threshold, and AP rheobase were also not significantly different at the NRs of the two types of fibers in the sciatic nerves. In comparison with Aα/ß-afferent fibers, Aα-efferent fibers in the sciatic nerves show higher amplitude and broader width of APs at their NRs. At the NRs of both types of fibers, depolarizing voltages evoked transient inward currents followed by non-inactivating outward currents, and the inward currents and non-inactivating outward currents at the NRs were not significantly different between the two types of fibers. Using AP-clamp, inward currents during AP upstroke were found to be insignificant difference, but amplitudes of non-inactivating outward currents during AP repolarization were significantly lower at the NRs of Aα-efferent fibers than at the NRs of Aα/ß-afferent fibers in the sciatic nerves. Collectively, saltatory conduction, ionic currents, and intrinsic electrophysiological properties at the NRs of Aα/ß-afferent fibers and Aα-efferent fibers in the sciatic nerves are generally similar, but some differences were also observed.
Asunto(s)
Fibras Nerviosas Mielínicas , Conducción Nerviosa , Ratas , Animales , Fibras Nerviosas Mielínicas/fisiología , Nódulos de Ranvier , Potenciales de Acción/fisiología , Nervio Ciático/fisiologíaRESUMEN
Existing axonal finite element models do not consider sex morphological differences or the fidelity in dynamic input. To facilitate a systematic investigation into the micromechanics of diffuse axonal injury, we develop a parameterized modeling approach for automatic and efficient generation of sex-specific axonal models according to specified geometrical parameters. Baseline female and male axonal models in the corpus callosum with random microtubule (MT) gap configurations are generated for model calibration and evaluation. They are then used to simulate a realistic tensile loading consisting of both a loading and a recovery phase (to return to an initial undeformed state) generated from dynamic corpus callosum fiber strain in a real-world head impact simulation. We find that MT gaps and the dynamic recovery phase are both critical to successfully reproduce MT undulation as observed experimentally, which has not been reported before. This strengthens confidence in model dynamic responses. A statistical approach is further employed to aggregate axonal responses from a large sample of random MT gap configurations for both female and male axonal models (n = 10,000 each). We find that peak strains in MTs and the Ranvier node and associated neurofilament failures in female axons are substantially higher than those in male axons because there are fewer MTs in the former and also because of the random nature of MT gap locations. Despite limitations in various model assumptions as a result of limited experimental data currently available, these findings highlight the need to systematically characterize MT gap configurations and to ensure a realistic model input for axonal dynamic simulations. Finally, this study may offer fresh and improved insight into the biomechanical basis of sex differences in brain injury, and sets the stage for more systematic investigations at the microscale in the future, both numerically and experimentally.
Asunto(s)
Lesiones Encefálicas , Caracteres Sexuales , Femenino , Masculino , Humanos , Análisis de Elementos Finitos , Axones/fisiología , Nódulos de RanvierRESUMEN
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.
Asunto(s)
Axones , Nódulos de Ranvier , Humanos , Nódulos de Ranvier/patología , Vaina de Mielina , Neuroglía , Nervios PeriféricosRESUMEN
The nodes of Ranvier (NoR) are essential domains for nerve conduction and their disruption plays a key role in the pathophysiology of immune-mediated neuropathies. Our understanding of the specialized nodal regions and the immune mechanisms that affect them is growing and has led to the update of peripheral neuropathy classification to include the autoimmune nodopathies, defined by the site of the autoimmune attack. Autoantibodies directed against molecules of the nodal region (as neurofascin-140/186, neurofascin-155, contactin-1, contactin-associated protein 1, contactin-associated protein 2, gangliosides, LGI4, or myelin-associated glycoprotein), macrophage-induced paranodal demyelination, and phenotypic changes of the nodal domains of Schwann cells have been identified as key mechanisms in the pathogenesis of the autoimmune neuropathies. This review explores the current knowledge of the autoimmune vulnerability of the NoR, including the underlying mechanisms leading to dysfunction in the diverse autoimmune disorders.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico , Nódulos de Ranvier , Humanos , Células de Schwann , Enfermedades del Sistema Nervioso Periférico/patología , Autoanticuerpos , Contactinas/metabolismoRESUMEN
The node of Ranvier is the key element in saltatory conduction along myelinated axons, but its specific protein organization remains elusive in the human species. To shed light on nanoscale anatomy of the human node of Ranvier in health and disease, we assessed human nerve biopsies of patients with polyneuropathy by super-resolution fluorescence microscopy. We applied direct stochastic optical reconstruction microscopy (dSTORM) and supported our data by high-content confocal imaging combined with deep learning-based analysis. As a result, we revealed a â¼ 190 nm periodic protein arrangement of cytoskeletal proteins and axoglial cell adhesion molecules in human peripheral nerves. In patients with polyneuropathy, periodic distances increased at the paranodal region of the node of Ranvier, both at the axonal cytoskeleton and at the axoglial junction. In-depth image analysis revealed a partial loss of proteins of the axoglial complex (Caspr-1, neurofascin-155) in combination with detachment from the cytoskeletal anchor protein ß2-spectrin. High content analysis showed that such paranodal disorganization occurred especially in acute and severe axonal neuropathy with ongoing Wallerian degeneration and related cytoskeletal damage. We provide nanoscale and protein-specific evidence for the prominent, but vulnerable role of the node of Ranvier for axonal integrity. Furthermore, we show that super-resolution imaging can identify, quantify and map elongated periodic protein distances and protein interaction in histopathological tissue samples. We thus introduce a promising tool for further translational applications of super resolution microscopy.
Asunto(s)
Polineuropatías , Nódulos de Ranvier , Humanos , Nódulos de Ranvier/metabolismo , Nódulos de Ranvier/ultraestructura , Axones/metabolismo , Proteínas del Citoesqueleto/metabolismo , Nervios Periféricos/metabolismoRESUMEN
PURPOSE OF REVIEW: Recognition of node of Ranvier as the site of injury in inflammatory neuropathies contributed to discovery of antibodies against the nodal/paranodal structures. These antibodies mediate a unique type of inflammatory neuropathies that are different from typical chronic inflammatory demyelinating polyneuropathy. This review discusses the advancements made in the field of autoimmune neuropathies secondary to antibodies to nodal and paranodal proteins. RECENT FINDINGS: Neuropathies caused by antibodies to nodal-paranodal antigens including neurofascin 186, neurofascin 155, contactin1, and contactin-associated protein1 were termed as autoimmune nodopathies (AN) in 2021. Since the initial description almost a decade ago, newer cohorts have expanded the clinical spectrum of AN. In addition to IgG4, other subclasses of IgG such as IgG1/IgG3 have been identified, particularly in relation to acute presentations and anti-pan neurofascin antibody disease. In vitro and in vivo studies have also supported antibody-mediated pathogenicity of many of these biomarkers. Antibodies to nodal-paranodal antigens have emerged as a biomarker for a novel type of immune-mediated neuropathies. These antibodies have distinct pathogenic mechanisms and produce a unique set of clinicopathologic features. Their clinical profile and treatment may also vary depending on the antibody isotype. B cell depleting therapies are effective in managing some of these patients.
Asunto(s)
Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Nódulos de Ranvier , Humanos , Nódulos de Ranvier/metabolismo , Nódulos de Ranvier/patología , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/uso terapéutico , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/uso terapéutico , Autoanticuerpos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Inmunoglobulina GRESUMEN
Along myelinated axons, Shaker-type potassium channels (Kv1) accumulate at high density in the juxtaparanodal region, directly adjacent to the paranodal axon-glia junctions that flank the nodes of Ranvier. However, the mechanisms that control the clustering of Kv1 channels, as well as their function at this site, are still poorly understood. Here we demonstrate that axonal ADAM23 is essential for both the accumulation and stability of juxtaparanodal Kv1 complexes. The function of ADAM23 is critically dependent on its interaction with its extracellular ligands LGI2 and LGI3. Furthermore, we demonstrate that juxtaparanodal Kv1 complexes affect the refractory period, thus enabling high-frequency burst firing of action potentials. Our findings not only reveal a previously unknown molecular pathway that regulates Kv1 channel clustering, but they also demonstrate that the juxtaparanodal Kv1 channels that are concealed below the myelin sheath, play a significant role in modifying axonal physiology.
Asunto(s)
Proteínas ADAM , Axones , Vaina de Mielina , Proteínas del Tejido Nervioso , Canales de Potasio con Entrada de Voltaje , Potenciales de Acción , Axones/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Vaina de Mielina/metabolismo , Neuroglía/metabolismo , Nódulos de Ranvier/metabolismo , Proteínas ADAM/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismoRESUMEN
Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratones , Animales , Humanos , Nódulos de Ranvier/metabolismo , Potasio/metabolismo , Neuronas/metabolismo , Oligodendroglía/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismoRESUMEN
Nodes of Ranvier play critical roles in the generation and transmission of action potentials. Alterations in node properties during pathology and/or development are known to affect the speed and quality of electrical transmission. From a modelling standpoint, nodes of Ranvier are often described by systems of ordinary differential equations neglecting or greatly simplifying their geometric structure. These approaches fail to accurately describe how fine scale alteration in the node geometry or in myelin thickness in the paranode region will impact action potential generation and transmission. Here, we rely on a finite element approximation to describe the three dimensional geometry of a node of Ranvier. With this, we are able to investigate how sensitive is the electrical response to alterations in the myelin sheath and paranode geometry. We could in particular investigate irregular loss of myelin, which might be more physiologically relevant than the uniform loss often described through simpler modelling approaches.
Asunto(s)
Vaina de Mielina , Nódulos de Ranvier , Vaina de Mielina/patología , Vaina de Mielina/fisiología , Nódulos de Ranvier/fisiología , Axones/fisiología , Potenciales de Acción/fisiologíaRESUMEN
Oligodendrocytes, the myelinating cells of the CNS, promote rapid action potential conduction along axons. Changes in the geometry of gaps between myelin segments, known as nodes of Ranvier, affect the conduction speed of neuronal impulses and can ultimately alter neural synchronization and circuit function. In contrast to synaptic plasticity, much less is known about how neural activity may affect node of Ranvier structure. Recently, perinodal astrocytes have been shown to remodel nodes of Ranvier by regulating thrombin proteolysis, but it is not known whether neural activity influences this process. To test this hypothesis, we used transgenic mice with astrocytic expression of a dominant-negative vesicle-associated membrane protein 2 ([gfap]dnVAMP2) to reduce exocytosis of thrombin inhibitors, modulating astrocytic regulation of paranodal loop attachment to induce nodal remodeling, under normal conditions and in adult mice maintained in darkness from postnatal day 40 (P40) to P70. This mechanism of nodal lengthening proceeded normally following binocular visual deprivation (BVD). The effect of BVD on nodal plasticity in animals with unimpaired astrocyte function has not been previously investigated. We find that when exocytosis from astrocytes was unimpaired, nodal gap length was not altered by BVD in adult mice. We conclude that if perinodal astrocytes participate in activity-dependent myelin remodeling through exocytosis, then, as with synaptic plasticity in the visual system, the process must be driven by alterations in neuronal firing other than those produced by BVD.
Asunto(s)
Nódulos de Ranvier , Trombina , Ratones , Animales , Nódulos de Ranvier/metabolismo , Trombina/metabolismo , Nervio Óptico , Vaina de Mielina/metabolismo , Axones , Ratones TransgénicosRESUMEN
Background and objectives: Several autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) in the last few years. Then a new concept, autoimmune nodo-paranodopathies was proposed. Cases of Caspr1 autoantibodies are the most rare. Here we describe an anti-Caspr1 nodopathy patient, summarized his clinical, physiological and pathological features. Case presentation: We present the case of a 56-year-old male patient with proprioceptive loss, ataxia, coarse tremor and distal limb weakness without any painess and cranial involvement. Electrophysiological studies showed prolonged distal motor latencies, conduction slowing and reduced amplitude distal compound muscle action potential (CMAP) amplitude. Antibodies against the nodes of Ranvier in serum samples revealed a positive finding for the anti-Caspr1 antibody (1:10).Myelinated fiber loss could be revealed in nerve biopsy. Longitudinal ultrathin sections of the nodal region was discovered in electron microscope, the paranodal/nodal architecture was destructed. It was lack of transverse bands and enlargement of the space between the axon and the paranodal loops was seen. The patient improved obviously after three times immunoadsorption(IA) therapy. Conclusion: Anti-Caspr1 nodopathy patient may present atypical symptoms without any neuropathic pain and cranial palsy. The destruction of paranodal/nodal architecture could be observed in nerve biopsy, which may be caused by the lost of axoglial complex formed by NF155, CNTN1 and Caspr1. Antibodies detection is important for the diagnosis, while IA therapy could be regarded as an option for the patients allergic to rituximab (RTX).
Asunto(s)
Factores de Crecimiento Nervioso , Nódulos de Ranvier , Autoanticuerpos , Moléculas de Adhesión Celular/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Rituximab/metabolismoRESUMEN
The nodes of Ranvier are unmyelinated gaps in the axon, important for the efficient transmission of action potentials. Despite the identification of several glycoproteins involved in node formation and maintenance, glycans' structure and formation in the node remain unclear. Previously, we developed a recombinant lectin from the Clostridium botulinum neurotoxin complex, specific to the galactose and N-acetylgalactosamine terminal epitopes (Gg). Gg stained Neuro2a cells. Here, we show Gg punctuate staining in mouse brain cryosections. Thus, we hypothesized that Gg could help study glycans in the node of Ranvier. Lectin histochemistry on mouse brain cryosections confirmed that Gg binds specifically to the node of Ranvier in the central nervous system (CNS). Using a combination of lectin blotting, glycosidase treatment on tissue sections, and lectin histochemistry, Gg ligands were identified as α-galactose terminal glycoproteins in the perinodal extracellular matrix. Furthermore, we detected the spatiotemporal distribution of galactosylated glycans in the CNS node of Ranvier in mouse brain tissues at different postnatal times. Finally, we observed impaired clustering of galactosylated glycans in the nodes during demyelination and remyelination in cuprizone-induced demyelination and remyelination mouse model. In conclusion, Gg can serve as a novel brain imaging tool in glycobiology and report glycoprotein formation and alterations in the CNS node of Ranvier. Our findings might serve as a first step to establish the role of glycans in the node of Ranvier.