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Semergen 2018Myasthenia gravis is one of the most common disorders that affect neuromuscular transmission. It is currently one of the most understood and characterised autoimmune...
Myasthenia gravis is one of the most common disorders that affect neuromuscular transmission. It is currently one of the most understood and characterised autoimmune disorders Its typical symptoms are fluctuating weakness and fatigue that affects a combination of ocular muscles, bulbar functions, as well as limb and respiratory muscles, which are due to an immune attack against the postsynaptic membrane of the neuromuscular junction. The diagnosis of myasthenia gravis is based on clinical and serological test. It is a disease that can be effectively controlled with the current therapeutic lines, even achieving a complete remission. An update of this interesting disorder is now presented.
Topics: Humans; Myasthenia Gravis; Neuromuscular Junction; Synaptic Membranes
PubMed: 29555378
DOI: 10.1016/j.semerg.2018.01.003 -
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 -
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 -
Cell Aug 2016Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange...
Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Binding of SynGAP to PSD-95 induces phase separation of the complex, forming highly concentrated liquid-like droplets reminiscent of the PSD. The multivalent nature of the SynGAP/PSD-95 complex is critical for the phase separation to occur and for proper activity-dependent SynGAP dispersions from the PSD. In addition to revealing a dynamic anchoring mechanism of SynGAP at the PSD, our results also suggest a model for phase-transition-mediated formation of PSD.
Topics: Animals; Disks Large Homolog 4 Protein; HEK293 Cells; HeLa Cells; Hippocampus; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Neuronal Plasticity; Neurons; Phase Transition; Post-Synaptic Density; Protein Conformation, alpha-Helical; Protein Multimerization; Rats; ras GTPase-Activating Proteins
PubMed: 27565345
DOI: 10.1016/j.cell.2016.07.008 -
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 -
Nature Neuroscience Jun 2023Endocannabinoids are among the most powerful modulators of synaptic transmission throughout the nervous system, and yet little is understood about the release of...
Endocannabinoids are among the most powerful modulators of synaptic transmission throughout the nervous system, and yet little is understood about the release of endocannabinoids from postsynaptic compartments. Here we report an unexpected finding that endocannabinoid release requires synucleins, key contributors to Parkinson's disease. We show that endocannabinoids are released postsynaptically by a synuclein-dependent and SNARE-dependent mechanism. Specifically, we found that synuclein deletion blocks endocannabinoid-dependent synaptic plasticity; this block is reversed by postsynaptic expression of wild-type but not of mutant α-synuclein. Whole-cell recordings and direct optical monitoring of endocannabinoid signaling suggest that the synuclein deletion specifically blocks endocannabinoid release. Given the presynaptic role of synucleins in regulating vesicle lifecycle, we hypothesize that endocannabinoids are released via a membrane interaction mechanism. Consistent with this hypothesis, postsynaptic expression of tetanus toxin light chain, which cleaves synaptobrevin SNAREs, also blocks endocannabinoid-dependent signaling. The unexpected finding that endocannabinoids are released via a synuclein-dependent mechanism is consistent with a general function of synucleins in membrane trafficking and adds a piece to the longstanding puzzle of how neurons release endocannabinoids to induce synaptic plasticity.
Topics: Endocannabinoids; Signal Transduction; Synaptic Transmission; Neurons; Cell Communication
PubMed: 37248337
DOI: 10.1038/s41593-023-01345-0 -
Molecular and Cellular Neurosciences Mar 2023Molecular interactions between pre- and postsynaptic membranes play critical roles during the development, function and maintenance of synapses. Synaptic interactions... (Review)
Review
Molecular interactions between pre- and postsynaptic membranes play critical roles during the development, function and maintenance of synapses. Synaptic interactions are mediated by cell surface receptors that may be held in place by trans-synaptic adhesion or intracellular binding to membrane-associated scaffolding and signaling complexes. Despite their role in stabilizing synaptic contacts, synaptic adhesion molecules undergo turnover and degradation during all stages of a neuron's life. Here we review current knowledge about membrane trafficking mechanisms that regulate turnover of synaptic adhesion molecules and the functional significance of turnover for synapse development and function. Based on recent proteomics, genetics and imaging studies, synaptic adhesion molecules exhibit remarkably high turnover rates compared to other synaptic proteins. Degradation occurs predominantly via endolysosomal mechanisms, with little evidence for roles of proteasomal or autophagic degradation. Basal turnover occurs both during synaptic development and maintenance. Neuronal activity typically stabilizes synaptic adhesion molecules while downregulating neurotransmitter receptors based on turnover. In conclusion, constitutive turnover of synaptic adhesion molecules is not a necessarily destabilizing factor, but a basis for the dynamic regulation of trans-synaptic interactions during synapse formation and maintenance.
Topics: Synapses; Synaptic Membranes; Neurons; Cell Adhesion; Signal Transduction; Cell Adhesion Molecules, Neuronal
PubMed: 36649812
DOI: 10.1016/j.mcn.2023.103816 -
Neuroscience Nov 2019SNARE-complexes drive the fusion of membrane-bound vesicles with target membranes or with each other (homotypic fusion). The SNARE-proteins are subdivided into Q, Q, Q... (Review)
Review
SNARE-complexes drive the fusion of membrane-bound vesicles with target membranes or with each other (homotypic fusion). The SNARE-proteins are subdivided into Q, Q, Q and R-SNAREs depending on their position in the four-helical SNARE-bundle. Here, we review the SNAP-25 protein sub-family, which includes both the Q and Q SNARE-domains within a single protein. In vertebrates, this sub-family consists of SNAP-25, SNAP-23, SNAP-29 and SNAP-47, named for their apparent molecular weights. SNAP-25 and SNAP-23 are specialized for driving regulated exocytosis. SNAP-25 performs this function in the nervous system, and in neuroendocrine cells, where fast Ca-dependent triggering is required in order to synchronize release with an electrical signal, whereas SNAP-23 drives regulated exocytosis in most other cases that have been studied, e.g. platelet exocytosis or glucose transporter trafficking. SNAP-25 is regulated by alternative splicing, phosphorylation and by G-protein binding, and it regulates Ca-channels, neuronal survival and postsynaptic spine development. SNAP-23 is primarily regulated by phosphorylation within the linker connecting Q to Q. Cross-rescue experiments show that SNAP-25 and SNAP-23 can (at least partly) substitute for each other, whereas SNAP-29 and SNAP-47 cannot. SNAP-29 is present on intracellular membranes and performs functions in autophagosome-to-lysosome fusion, among others. An overlapping function for SNAP-47 was described; in addition, SNAP-47 mediates postsynaptic AMPA-receptor insertion. Overall, the presence of two SNARE-domains confers members of this family the ability to associate to different Q and R-SNAREs and drive diverse membrane fusion reactions; one member of the family, SNAP-25, has been devoted entirely to Ca-triggered fusion and has taken on a number of additional, regulatory roles.
Topics: Animals; Exocytosis; Humans; Neurons; Synaptosomal-Associated Protein 25
PubMed: 30267828
DOI: 10.1016/j.neuroscience.2018.09.020 -
Neuropharmacology Jun 2020The flexibility of neuronal networks is believed to rely mainly on the plasticity of excitatory synapses. However, like their excitatory counterparts, inhibitory... (Review)
Review
The flexibility of neuronal networks is believed to rely mainly on the plasticity of excitatory synapses. However, like their excitatory counterparts, inhibitory synapses also undergo several forms of synaptic plasticity. This review examines recent advances in the understanding of the molecular mechanisms leading to postsynaptic GABAergic plasticity. Specifically, modulation of GABAA receptor (GABAAR) number at postsynaptic sites plays a key role, with the interaction of GABAARs with the scaffold protein gephyrin and other postsynaptic scaffold/regulatory proteins having particular importance. Our understanding of these molecular interactions are progressing, based on recent insights into the processes of GABAAR lateral diffusion, gephyrin dynamics, and gephyrin nanoscale organization. This article is part of the special issue entitled 'Mobility and trafficking of neuronal membrane proteins'.
Topics: Animals; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Humans; Membrane Proteins; Neuronal Plasticity; Receptors, GABA-A; Synapses; Synaptic Potentials
PubMed: 31108109
DOI: 10.1016/j.neuropharm.2019.05.020