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Journal of Clinical Medicine Apr 2021Myasthenia gravis (MG) is an autoimmune neuromuscular disorder which is characterized by presence of antibodies against acetylcholine receptors (AChRs) or other proteins... (Review)
Review
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder which is characterized by presence of antibodies against acetylcholine receptors (AChRs) or other proteins of the postsynaptic membrane resulting in damage to postsynaptic membrane, decreased number of AChRs or blocking of the receptors by autoantibodies. A number of drugs such as immune checkpoint inhibitors, penicillamine, tyrosine kinase inhibitors and interferons may induce de novo MG by altering the immune homeostasis mechanisms which prevent emergence of autoimmune diseases such as MG. Other drugs, especially certain antibiotics, antiarrhythmics, anesthetics and neuromuscular blockers, have deleterious effects on neuromuscular transmission, resulting in increased weakness in MG or MG-like symptoms in patients who do not have MG, with the latter usually being under medical circumstances such as kidney failure. This review summarizes the drugs which can cause de novo MG, MG exacerbation or MG-like symptoms in nonmyasthenic patients.
PubMed: 33917535
DOI: 10.3390/jcm10071537 -
Science China. Life Sciences Jul 2020Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments to ensure that a wide variety of cellular activities occur in a... (Review)
Review
Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments to ensure that a wide variety of cellular activities occur in a spatially and temporally controlled manner. The molecular mechanisms underlying the dynamics of membrane-bound organelles, such as their fusion and fission, vesicle-mediated trafficking and membrane contactmediated inter-organelle interactions, have been extensively characterized. However, the molecular details of the assembly and functions of membraneless compartments remain elusive. Mounting evidence has emerged recently that a large number of membraneless compartments, collectively called biomacromolecular condensates, are assembled via liquid-liquid phase separation (LLPS). Phase-separated condensates participate in various biological activities, including higher-order chromatin organization, gene expression, triage of misfolded or unwanted proteins for autophagic degradation, assembly of signaling clusters and actin- and microtubule-based cytoskeletal networks, asymmetric segregations of cell fate determinants and formation of pre- and post-synaptic density signaling assemblies. Biomacromolecular condensates can transition into different material states such as gel-like structures and solid aggregates. The material properties of condensates are crucial for fulfilment of their distinct functions, such as biochemical reaction centers, signaling hubs and supporting architectures. Cells have evolved multiple mechanisms to ensure that biomacromolecular condensates are assembled and disassembled in a tightly controlled manner. Aberrant phase separation and transition are causatively associated with a variety of human diseases such as neurodegenerative diseases and cancers. This review summarizes recent major progress in elucidating the roles of LLPS in various biological pathways and diseases.
Topics: Animals; Autophagy; Cell Membrane; Cell Physiological Phenomena; Chromatin; Gene Expression; Humans; Kinetics; Neoplasms; Neurodegenerative Diseases; Organelles; Phase Transition; Protein Folding; Proteins; Proteolysis; Surface Properties
PubMed: 32548680
DOI: 10.1007/s11427-020-1702-x -
Nature Jul 2021Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into...
Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins. It is unclear whether neurexin-cerebellin-GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. Here we show in hippocampal synapses, that binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. Specifically, neurexin-1-cerebellin-2 and neurexin-3-cerebellin-2 complexes differentially regulate NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors by activating distinct postsynaptic GluD1 effector signals. Of note, minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-3 is encoded by their alternatively spliced splice site 4 sequences, whereas the regulatory functions of postsynaptic GluD1 are mediated by conserved cytoplasmic sequence motifs spanning 5-13 residues. Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture and directly converts extracellular neurexin-cerebellin signals into postsynaptic receptor responses.
Topics: Amino Acid Motifs; Animals; Calcium-Binding Proteins; Cell Membrane; Excitatory Postsynaptic Potentials; Female; Glutamate Dehydrogenase; Male; Mice; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Protein Precursors; Receptors, AMPA; Receptors, Ionotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synapses
PubMed: 34135511
DOI: 10.1038/s41586-021-03661-6 -
Nature Feb 2021In the adult hippocampus, synapses are constantly formed and eliminated. However, the exact function of synapse elimination in the adult brain, and how it is regulated,...
In the adult hippocampus, synapses are constantly formed and eliminated. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we show that astrocytic phagocytosis is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function.
Topics: Aging; Animals; Astrocytes; CA1 Region, Hippocampal; Excitatory Postsynaptic Potentials; Female; Homeostasis; Inhibitory Postsynaptic Potentials; Male; Membrane Proteins; Memory; Mice; Neural Pathways; Neuronal Plasticity; Phagocytosis; Synapses
PubMed: 33361813
DOI: 10.1038/s41586-020-03060-3 -
Molecular Immunology Nov 2022Myasthenia gravis is a neuromuscular disease associated with antibodies against components of the neuromuscular junction, most often against the acetylcholine receptor... (Review)
Review
Myasthenia gravis is a neuromuscular disease associated with antibodies against components of the neuromuscular junction, most often against the acetylcholine receptor (AChR). Although several mechanisms have been postulated to explain how these autoantibodies can lead to the pathology of the disease, convincing evidence suggests that destruction of the receptor-bearing postsynaptic membrane by complement membrane attack complex is of central importance. In this review, evidence for the importance of complement, and possible relationships between autoantigen, autoantibodies, complement activation, and the destruction of the membrane are discussed. More recent insights from the results of the complement-inhibiting therapeutic antibody eculizumab are also described, and the mechanisms connecting antibody binding to complement activation are considered from a structural viewpoint.
Topics: Autoantibodies; Autoantigens; Complement Membrane Attack Complex; Complement System Proteins; Humans; Myasthenia Gravis; Receptors, Cholinergic
PubMed: 36063582
DOI: 10.1016/j.molimm.2022.08.018 -
Archives of Biochemistry and Biophysics Apr 2021The cholinergic neuromuscular junction is the paradigm peripheral synapse between a motor neuron nerve ending and a skeletal muscle fiber. In vertebrates, acetylcholine... (Review)
Review
The cholinergic neuromuscular junction is the paradigm peripheral synapse between a motor neuron nerve ending and a skeletal muscle fiber. In vertebrates, acetylcholine is released from the presynaptic site and binds to the nicotinic acetylcholine receptor at the postsynaptic membrane. A variety of pathologies among which myasthenia gravis stands out can impact on this rapid and efficient signaling mechanism, including autoimmune diseases affecting the nicotinic receptor or other synaptic proteins. Cholesterol is an essential component of biomembranes and is particularly rich at the postsynaptic membrane, where it interacts with and modulates many properties of the nicotinic receptor. The profound changes inflicted by myasthenia gravis on the postsynaptic membrane necessarily involve cholesterol. This review analyzes some aspects of myasthenia gravis pathophysiology and associated postsynaptic membrane dysfunction, including dysregulation of cholesterol metabolism in the myocyte brought about by antibody-receptor interactions. In addition, given the extensive therapeutic use of statins as the typical cholesterol-lowering drugs, we discuss their effects on skeletal muscle and the possible implications for MG patients under chronic treatment with this type of compound.
Topics: Animals; Cholesterol; Humans; Myasthenia Gravis; Neuromuscular Junction
PubMed: 33548213
DOI: 10.1016/j.abb.2021.108788 -
Science (New York, N.Y.) Mar 2024Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the...
Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory synapses on a timescale of seconds during behavior.
Topics: Animals; Mice; Endocannabinoids; Neuronal Plasticity; Synapses; Synaptic Transmission; Calcium Signaling; CA1 Region, Hippocampal; Inhibitory Postsynaptic Potentials; Receptor, Cannabinoid, CB1; Male; Female; Mice, Knockout
PubMed: 38422134
DOI: 10.1126/science.adk3863 -
Handbook of Clinical Neurology 2023Myasthenia gravis is an autoimmune disorder caused by antibodies against elements in the postsynaptic membrane at the neuromuscular junction, which leads to muscle... (Review)
Review
Myasthenia gravis is an autoimmune disorder caused by antibodies against elements in the postsynaptic membrane at the neuromuscular junction, which leads to muscle weakness. Congenital myasthenic syndromes are rare and caused by mutations affecting pre- or postsynaptic function at the neuromuscular synapse and resulting in muscle weakness. MG has a prevalence of 150-250 and an annual incidence of 8-10 individuals per million. The majority has disease onset after age 50 years. Juvenile MG with onset in early childhood is more common in East Asia. MG is subgrouped according to type of pathogenic autoantibodies, age of onset, thymus pathology, and generalization of muscle weakness. More than 80% have antibodies against the acetylcholine receptor. The remaining have antibodies against MuSK, LRP4, or postsynaptic membrane antigens not yet identified. A thymoma is present in 10% of MG patients, and more than one-third of thymoma patients develop MG as a paraneoplastic condition. Immunosuppressive drug therapy, thymectomy, and symptomatic drug therapy with acetylcholine esterase inhibitors represent cornerstones in the treatment. The prognosis is good, with the majority of patients having mild or moderate symptoms only. Most congenital myasthenic syndromes are due to dysfunction in the postsynaptic membrane. Symptom debut is in early life. Symptomatic drug treatment has sometimes a positive effect.
Topics: Child, Preschool; Humans; Middle Aged; Myasthenic Syndromes, Congenital; Thymoma; Myasthenia Gravis; Muscle Weakness; Autoantibodies; Thymus Neoplasms
PubMed: 37562891
DOI: 10.1016/B978-0-323-98818-6.00010-8