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Journal of Neuroimmunology Dec 2021The acquired chronic demyelinating neuropathies include a growing number of disease entities that have characteristic, often overlapping, clinical presentations,... (Review)
Review
The acquired chronic demyelinating neuropathies include a growing number of disease entities that have characteristic, often overlapping, clinical presentations, mediated by distinct immune mechanisms, and responding to different therapies. After the discovery in the early 1980s, that the myelin associated glycoprotein (MAG) is a target antigen in an autoimmune demyelinating neuropathy, assays to measure the presence of anti-MAG antibodies were used as the basis to diagnose the anti-MAG neuropathy. The route was open for describing the clinical characteristics of this new entity as a chronic distal large fiber sensorimotor neuropathy, for studying its pathogenesis and devising specific treatment strategies. The initial use of chemotherapeutic agents was replaced by the introduction in the late 1990s of rituximab, a monoclonal antibody against CD20 B-cells. Since then, other anti-B cells agents have been introduced. Recently a novel antigen-specific immunotherapy neutralizing the anti-MAG antibodies with a carbohydrate-based ligand mimicking the natural HNK-1 glycoepitope has been described.
Topics: Adenine; Animals; Autoantibodies; Autoantigens; B-Lymphocyte Subsets; CD57 Antigens; Demyelinating Autoimmune Diseases, CNS; Epitopes; Gait Disorders, Neurologic; Humans; Immunosuppressive Agents; Immunotherapy; Lenalidomide; Mammals; Mice; Molecular Mimicry; Myelin Sheath; Myelin-Associated Glycoprotein; Nerve Fibers, Myelinated; Nervous System Autoimmune Disease, Experimental; Paraproteinemias; Paraproteins; Piperidines; Plasma Exchange; Polyradiculoneuropathy; Ranvier's Nodes; Rats; Rituximab
PubMed: 34610502
DOI: 10.1016/j.jneuroim.2021.577725 -
Neuropsychopharmacology : Official... Sep 2023Differential expression of myelin-related genes and changes in myelin thickness have been demonstrated in mice after chronic psychosocial stress, a risk factor for...
Differential expression of myelin-related genes and changes in myelin thickness have been demonstrated in mice after chronic psychosocial stress, a risk factor for anxiety disorders. To determine whether and how stress affects structural remodeling of nodes of Ranvier, another form of myelin plasticity, we developed a 3D reconstruction analysis of node morphology in C57BL/6NCrl and DBA/2NCrl mice. We identified strain-dependent effects of chronic social defeat stress on node morphology in the medial prefrontal cortex (mPFC) gray matter, including shortening of paranodes in C57BL/6NCrl stress-resilient and shortening of node gaps in DBA/2NCrl stress-susceptible mice compared to controls. Neuronal activity has been associated with changes in myelin thickness. To investigate whether neuronal activation is a mechanism influencing also node of Ranvier morphology, we used DREADDs to repeatedly activate the ventral hippocampus-to-mPFC pathway. We found reduced anxiety-like behavior and shortened paranodes specifically in stimulated, but not in the nearby non-stimulated axons. Altogether, our data demonstrate (1) nodal remodeling of the mPFC gray matter axons after chronic stress and (2) axon-specific regulation of paranodes in response to repeated neuronal activity in an anxiety-associated pathway. Nodal remodeling may thus contribute to aberrant circuit function associated with anxiety disorders.
Topics: Mice; Animals; Mice, Inbred C57BL; Mice, Inbred DBA; Anxiety; Anxiety Disorders; Stress, Psychological; Prefrontal Cortex
PubMed: 36949148
DOI: 10.1038/s41386-023-01568-6 -
The Journal of Clinical Investigation Apr 2023Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal...
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.
Topics: Mice; Animals; Humans; Ranvier's Nodes; Potassium; Neurons; Oligodendroglia; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis
PubMed: 36719741
DOI: 10.1172/JCI164223 -
Acta Neuropathologica Nov 2022Despite being a major health concern, little is known about the pathophysiological changes that underly concussion. Nonetheless, emerging evidence suggests that...
Despite being a major health concern, little is known about the pathophysiological changes that underly concussion. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage-gated sodium channels (NaChs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain's network signaling machinery, changes in their integrity have not been studied in context with DAI. Here, we utilized a clinically relevant swine model of concussion that induces evolving axonal pathology, demonstrated by accumulation of amyloid precursor protein (APP) across the white matter. Over a two-week follow-up post-concussion with this model, we found widespread loss of NaCh isoform 1.6 (Nav1.6), progressive increases in NOR length, the appearance of void and heminodes and loss of βIV-spectrin, ankyrin G, and neurofascin 186 or their collective diffusion into the paranode. Notably, these changes were in close proximity, yet distinct from APP-immunoreactive swollen axonal profiles, potentially representing a unique, newfound phenotype of axonal pathology in DAI. Since concussion in humans is non-fatal, the clinical relevance of these findings was determined through examination of post-mortem brain tissue from humans with higher levels of acute traumatic brain injury. Here, a similar loss of Nav1.6 and changes in NOR structures in brain white matter were observed as found in the swine model of concussion. Collectively, this widespread and progressive disruption of NaChs and NOR appears to be a form of sodium channelopathy, which may represent an important substrate underlying brain network dysfunction after concussion.
Topics: Amyloid beta-Protein Precursor; Animals; Ankyrins; Axons; Brain Concussion; Brain Injuries; Humans; Protein Isoforms; Ranvier's Nodes; Sodium; Sodium Channels; Spectrin; Swine
PubMed: 36107227
DOI: 10.1007/s00401-022-02498-1 -
The Journal of Comparative Neurology Feb 2017The node of Ranvier is a functionally important site on the myelinated axon where sodium channels are clustered and regeneration of action potentials occurs, allowing...
The node of Ranvier is a functionally important site on the myelinated axon where sodium channels are clustered and regeneration of action potentials occurs, allowing fast saltatory conduction of action potentials. Early ultrastructural studies have revealed the presence of "glia" or "astrocytes" at the nodes. NG2 cells, also known as oligodendrocyte precursor cells or polydendrocytes, which are a resident glial cell population in the mature mammalian central nervous system that is distinct from astrocytes, have also been shown to extend processes that contact the nodes. However, the prevalence of the two types of glia at the node has remained unknown. We have used specific cell surface markers to examine the association of NG2 cells and astrocytes with the nodes of Ranvier in the optic nerve, corpus callosum, and spinal cord of young adult mice or rats. We show that more than 95% of the nodes in all three regions contained astrocyte processes, while 33-49% of nodes contained NG2 cell processes. NG2 cell processes were associated more frequently with larger nodes. A few nodes were devoid of glial apposition. Electron microscopy and stimulated emission depletion (STED) super-resolution microscopy confirmed the presence of dual glial insertion at some nodes and further revealed that NG2 cell processes contacted the nodal membrane at discrete points, while astrocytes had broader processes that surrounded the nodes. The study provides the first systematic quantitative analysis of glial cell insertions at central nodes of Ranvier. J. Comp. Neurol. 525:535-552, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Antigens; Astrocytes; Corpus Callosum; Fluorescent Antibody Technique; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Microscopy, Immunoelectron; Neural Stem Cells; Oligodendroglia; Optic Nerve; Proteoglycans; Ranvier's Nodes; Rats, Sprague-Dawley; Spinal Cord; Thoracic Vertebrae
PubMed: 27448245
DOI: 10.1002/cne.24083 -
The Neuroscientist : a Review Journal... Apr 2018Vertebrate nervous systems rely on rapid nerve impulse transmission to support their complex functions. Fast conduction depends on ensheathment of nerve axons by... (Review)
Review
Vertebrate nervous systems rely on rapid nerve impulse transmission to support their complex functions. Fast conduction depends on ensheathment of nerve axons by myelin-forming glia and the clustering of high concentrations of voltage-gated sodium channels (Nav) in the axonal gaps between myelinated segments. These gaps are the nodes of Ranvier. Depolarization of the axonal membrane initiates the action potential responsible for impulse transmission, and the Nav help ensure that this is restricted to nodes. In the central nervous system, the formation of nodes and the clustering of Nav in nodal complexes is achieved when oligodendrocytes extend their processes and ultimately ensheath axons with myelin. However, the mechanistic relationship between myelination and the formation of nodal complexes is unclear. Here we review recent work in the central nervous system that shows that axons, by assembling distinct cytoskeletal interfaces, are not only active participants in oligodendrocyte process migration but are also significant contributors to the mechanisms by which myelination causes Nav clustering. We also discuss how the segregation of membrane protein complexes through their interaction with distinct cytoskeletal complexes may play a wider role in establishing surface domains in axons.
Topics: Animals; Axons; Central Nervous System; Cytoskeleton; Ranvier's Nodes
PubMed: 28534438
DOI: 10.1177/1073858417710897 -
Neurochemistry International Nov 2019Demyelination diseases involving the central and peripheral nervous systems are etiologically heterogeneous with both cell-mediated and humoral immunities playing... (Review)
Review
Demyelination diseases involving the central and peripheral nervous systems are etiologically heterogeneous with both cell-mediated and humoral immunities playing pathogenic roles. Recently, autoantibodies against nodal and paranodal proteins, such as neurofascin186 (NF186), neurofascin155 (NF155), contactin-1 (CNTN1), contactin-associated protein 1 (CASPR1) and gliomedin, have been discovered in not only chronic demyelinating conditions, such as multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy, but also in acute demyelinating conditions, such as Guillain-Barré syndrome. Only a minority of these patients harbor anti-nodal/paranodal protein antibodies; however, these autoantibodies, especially IgG4 subclass autoantibodies to paranodal proteins, are associated with unique features and these conditions are collectively termed nodopathy or paranodopathy. Establishing a concept of IgG4-related nodopathy/paranodopathy contributes to diagnosis and treatment strategy because IgG4 autoantibody-related neurological diseases are often refractory to conventional immunotherapies. IgG4 does not fix complements, or internalize the target antigens, because IgG4 exists in a monovalent bispecific form in vivo. IgG4 autoantibodies can bock protein-protein interaction. Thus, the primary role of IgG4 anti-paranodal protein antibodies may be blockade of interactions between NF155 and CNTN1/CASPR1, leading to conduction failure, which is consistent with the sural nerve pathology presenting paranodal terminal loop detachment from axons with intact internodes in the absence of inflammation. However, it still remains to be elucidated how these autoantibodies belonging to the same IgG4 subclass can cause each IgG4 autoantibody-specific manifestation. Another important issue is to clarify the mechanism by which IgG4 antibodies to nodal/paranodal proteins emerge. IgG4 antibodies develop on chronic antigenic stimulation and can block antibodies that alleviate allergic inflammation by interfering with the binding of allergen-specific IgE to allergens. Thus, environmental antigens cross-reacting with nodal and paranodal proteins may warrant future study.
Topics: Animals; Autoantibodies; Cell Adhesion Molecules; Demyelinating Diseases; Humans; Nerve Growth Factors; Ranvier's Nodes
PubMed: 30582947
DOI: 10.1016/j.neuint.2018.12.011 -
Frontiers in Immunology 2018Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis... (Review)
Review
Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications.
Topics: Animals; Autoantibodies; Cell Adhesion Molecules; Cell Adhesion Molecules, Neuronal; Contactin 1; Humans; Mice; Nerve Growth Factors; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Ranvier's Nodes
PubMed: 29867996
DOI: 10.3389/fimmu.2018.01029 -
Journal of Anatomy Nov 2022Gangliosides are a family of sialic acid containing glycosphingolipids highly enriched in plasma membranes of the vertebrate nervous system. They are functionally... (Review)
Review
Gangliosides are a family of sialic acid containing glycosphingolipids highly enriched in plasma membranes of the vertebrate nervous system. They are functionally diverse in modulating nervous system integrity, notably at the node of Ranvier, and also act as receptors for many ligands including toxins and autoantibodies. They are synthesised in a stepwise manner by groups of glycosyl- and sialyltransferases in a developmentally and tissue regulated manner. In this review, we summarise and discuss data derived from transgenic mice with different transferase deficiencies that have been used to determine the role of glycolipids in the organisation of the node of Ranvier. Understanding their role at this specialised functional site is crucial to determining differential pathophysiology following directed genetic or autoimmune injury to peripheral nerve nodal or paranodal domains, and revealing the downstream consequences of axo-glial disruption.
Topics: Animals; Autoantibodies; Axons; Gangliosides; Glycolipids; Glycosyltransferases; Ligands; Mice; Mice, Transgenic; N-Acetylneuraminic Acid; Sialyltransferases
PubMed: 34605014
DOI: 10.1111/joa.13562 -
Journal of Neurology, Neurosurgery, and... Jan 2018This review summarises recent evidence supporting the involvement of the specialised nodal and perinodal domains (the paranode and juxtaparanode) of myelinated axons in... (Review)
Review
This review summarises recent evidence supporting the involvement of the specialised nodal and perinodal domains (the paranode and juxtaparanode) of myelinated axons in the pathology of acquired, inflammatory, peripheral neuropathies.The identification of new target antigens in the inflammatory neuropathies heralds a revolution in diagnosis, and has already begun to inform increasingly targeted and individualised therapies. Rapid progress in our basic understanding of the highly specialised nodal regions of peripheral nerves serves to strengthen the links between their unique microstructural identities, functions and pathologies. In this context, the detection of autoantibodies directed against nodal and perinodal targets is likely to be of increasing clinical importance. Antiganglioside antibodies have long been used in clinical practice as diagnostic serum biomarkers, and associate with specific clinical variants but not to the common forms of either acute or chronic demyelinating autoimmune neuropathy. It is now apparent that antibodies directed against several region-specific cell adhesion molecules, including neurofascin, contactin and contactin-associated protein, can be linked to phenotypically distinct peripheral neuropathies. Importantly, the immunological characteristics of these antibodies facilitate the prediction of treatment responsiveness.
Topics: Autoantibodies; Axons; Cell Adhesion Molecules; Contactin 1; Humans; Peripheral Nerves; Polyneuropathies; Ranvier's Nodes
PubMed: 28819062
DOI: 10.1136/jnnp-2016-315480