The agrin/muscle‐specific kinase pathway: New targets for autoimmune and genetic disorders at the neuromuscular junction
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Abstract The increasing understanding of the structural complexity of the neuromuscular junction (NMJ), and the processes that are important in its development, suggests many possible new disease targets. Here, we summarize briefly the genetic and autoimmune disorders that affect neuromuscular transmission, and the identified targets, including new evidence that antibodies to muscle‐specific receptor tyrosine kinase (MuSK) are involved in the pathogenesis of acetylcholine receptor (AChR) antibody–negative myasthenia gravis. We then review the development of the NMJ, focusing on the important roles of nerve‐derived agrin and MuSK in clustering of AChRs and other essential components of the NMJ. © 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 4–16, 2002Keywords:
Agrin
Neuromuscular transmission
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Purpose: Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction (NMJ) that causes impaired neuromuscular transmission and muscle weakness. Muscle Specific Kinase (MuSK) is recognized as the auto-antigen in about 10% of MG patients. Activation of MuSK by neural agrin is essential for acetylcholine receptor (AChR) clustering at the NMJ. Here we aimed to define the mechanisms by which anti-MuSK antibodies interfere with the postsynaptic AChR cluster.Conclusion: Anti-MuSK auto-antibodies cross-link and activate MuSK. This somehow causes the disassembly of large pre-existing AChR clusters.
Agrin
Neuromuscular transmission
Muscle weakness
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Myasthenia gravis (MG) is the most common disorder affecting the neuromuscular junction (NMJ). MG is frequently caused by autoantibodies against acetylcholine receptor (AChR) and a kinase critical for NMJ formation, MuSK; however, a proportion of MG patients are double-negative for anti-AChR and anti-MuSK antibodies. Recent studies in these subjects have identified autoantibodies against low-density lipoprotein receptor-related protein 4 (LRP4), an agrin receptor also critical for NMJ formation. LRP4 autoantibodies have not previously been implicated in MG pathogenesis. Here we demonstrate that mice immunized with the extracellular domain of LRP4 generated anti-LRP4 antibodies and exhibited MG-associated symptoms, including muscle weakness, reduced compound muscle action potentials (CMAPs), and compromised neuromuscular transmission. Additionally, fragmented and distorted NMJs were evident at both the light microscopic and electron microscopic levels. We found that anti-LRP4 sera decreased cell surface LRP4 levels, inhibited agrin-induced MuSK activation and AChR clustering, and activated complements, revealing potential pathophysiological mechanisms. To further confirm the pathogenicity of LRP4 antibodies, we transferred IgGs purified from LRP4-immunized rabbits into naive mice and found that they exhibited MG-like symptoms, including reduced CMAP and impaired neuromuscular transmission. Together, these data demonstrate that LRP4 autoantibodies induce MG and that LRP4 contributes to NMJ maintenance in adulthood.
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The number of acetylcholine receptors was determined in the neuromuscular junctions of eight patients with typical myasthenia gravis and in five controls, by means of (125)1-labeled alpha-bungarotoxin binding. The junctional acetylcholine receptors were reduced in the myasthenic muscles as compared with the controls. This reduction in receptors may account for the defect in neuromuscular transmission in myasthenia gravis.
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Abstract The increasing understanding of the structural complexity of the neuromuscular junction (NMJ), and the processes that are important in its development, suggests many possible new disease targets. Here, we summarize briefly the genetic and autoimmune disorders that affect neuromuscular transmission, and the identified targets, including new evidence that antibodies to muscle‐specific receptor tyrosine kinase (MuSK) are involved in the pathogenesis of acetylcholine receptor (AChR) antibody–negative myasthenia gravis. We then review the development of the NMJ, focusing on the important roles of nerve‐derived agrin and MuSK in clustering of AChRs and other essential components of the NMJ. © 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 4–16, 2002
Agrin
Neuromuscular transmission
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Here we present the first evidence that muscle-specific kinase (MuSK) antigen can cause myasthenia in animals. MuSK is expressed at the postsynaptic membranes of neuromuscular junctions (NMJ) and forms complexes with acetylcholine receptors (AChR) and rapsyn. MuSK is activated by agrin, which is released from motoneurons, and induces AChR clustering and subsequent formation of NMJ in embryos. Notably, autoantibodies against MuSK were found in a proportion of patients with generalized myasthenia gravis (MG) but without the characteristic AChR autoantibodies. However, MuSK autoantibodies had no known pathogenic potential, and animals immunized with purified MuSK proteins did not develop MG in former studies. In contrast, we have now injected rabbits with MuSK ectodomain protein in vivo and evoked a MG-like muscle weakness with a reduction of AChR clustering at the NMJ. Our results showed that MuSK is required for maintenance of synapses and that interference with that function by MuSK antibodies causes myasthenic weakness. In vitro, AChR clustering in myotubes is induced by agrin and agrin-independent inducers, which do not activate MuSK. Neither the receptor nor the activation mechanisms of AChR clustering induced by agrin-independent inducers has been identified with certainty, but MuSK autoantibodies in myasthenic animals inhibited both agrin and agrin-independent AChR clustering. MuSK plays multiple roles in pre-patterning of the postsynaptic membrane before innervation and formation of NMJ in embryos. Some of these mechanisms may also participate in the maintenance of mature NMJ. This model system would provide new knowledge about the molecular pathogenesis of MG and MuSK functions in mature NMJ.
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Agrin and its receptor MuSK are required for the formation of the postsynaptic apparatus at the neuromuscular junction (NMJ). In the current model the local deposition of agrin by the nerve and the resulting local activation of MuSK are responsible for creating and maintaining the postsynaptic apparatus including clusters of acetylcholine receptors (AChRs). Concomitantly, the release of acetylcholine (ACh) and the resulting depolarization disperses those postsynaptic structures that are not apposed by the nerve and thus not stabilized by agrin-MuSK signaling. Here we show that a miniaturized form of agrin, consisting of the laminin-binding and MuSK-activating domains, is sufficient to fully restore NMJs in agrin mutant mice when expressed by developing muscle. Although miniagrin is expressed uniformly throughout muscle fibers and induces ectopic AChR clusters, the size and the number of those AChR clusters contacted by the motor nerve increase during development. We provide experimental evidence that this is due to ACh, because the AChR agonist carbachol stabilizes AChR clusters in organotypic cultures of embryonic diaphragms. In summary, our results show that agrin function in NMJ development requires only two small domains, and that this function does not depend on the local deposition of agrin at synapses. Finally, they suggest a novel local function of ACh in stabilizing postsynaptic structures.
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Synaptic cleft
Motor Endplate
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This paper describes two condition caused by disfunction of neuromuscular transport: experimental autoimmune myasthenia gravis (EAMG) and Lambert-Eaton myasthenic syndrome (LEMS). EAMG can be caused by immunization with acetylcholine receptors (AChR). As in myasthenia gravis, anti-AChR antibodies reduce the number of these receptors, which impedes normal neuromuscular transmission. LEMS patients have normal AChR function: however there is a disfunction of acetylcholine release from the presynaptic terminals. This is due to the formation of antibodies against the voltage gated calcium channels on the presynaptic nerve terminals.
Neuromuscular transmission
Lambert-Eaton myasthenic syndrome
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