Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling

We investigated the influence of postsynaptic tyrosine kinase signaling in a mouse model of muscle‐specific kinase (MuSK) myasthenia gravis (MG). Mice administered repeated daily injections of IgG from MuSK MG patients developed impaired neuromuscular transmission due to progressive loss of acetylcholine receptor (AChR) from the postsynaptic membrane of the neuromuscular junction. In this model, anti‐MuSK‐positive IgG caused a reduction in motor endplate immunolabeling for phosphorylated Src‐Y418 and AChR β‐subunit‐Y390 before any detectable loss of MuSK or AChR from the endplate. Adeno‐associated viral vector (rAAV) encoding MuSK fused to enhanced green fluorescent protein (MuSK‐EGFP) was injected into the tibialis anterior muscle to increase MuSK synthesis. When mice were subsequently challenged with 11 daily injections of IgG from MuSK MG patients, endplates expressing MuSK‐EGFP retained more MuSK and AChR than endplates of contralateral muscles administered empty vector. Recordings of compound muscle action potentials from myasthenic mice revealed less impairment of neuromuscular transmission in muscles that had been injected with rAAV‐MuSK‐EGFP than contralateral muscles (empty rAAV controls). In contrast to the effects of MuSK‐EGFP, forced expression of rapsyn‐EGFP provided no such protection to endplate AChR when mice were subsequently challenged with MuSK MG IgG. In summary, the immediate in vivo effect of MuSK autoantibodies was to suppress MuSK‐dependent tyrosine phosphorylation of proteins in the postsynaptic membrane, while increased MuSK synthesis protected endplates against AChR loss. These results support the hypothesis that reduced MuSK kinase signaling initiates the progressive disassembly of the postsynaptic membrane scaffold in this mouse model of MuSK MG.

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“…; Otsuka et al. ). These findings suggest that interruption of agrin‐MuSK signaling activity might be sufficient to cause NMJ disassembly.…”

Section: Discussionmentioning

confidence: 97%

“…; Otsuka et al. ). Conversely, a forced increase in MuSK synthesis ameliorated these effects of MuSK autoantibodies in our mouse passive transfer model of MuSK MG.…”

Section: Discussionmentioning

confidence: 97%

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Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

et al. 2015

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“…77 Mice with MuSK-EAMG show the same EMG patterns reflecting ACh hypersensitivity, suggesting that the pathological conditions of patients could be faithfully reproduced in the animal MG models. 79,82 These studies revealed the mechanism by which ChE inhibitor treatment worsens symptoms in patients with MuSK-MG. 1), 81 MuSK antibodies might affect the interaction between MuSK and ColQ, and impair AChE activity.…”

Section: Effects Of Cholinesterase Inhibitorsmentioning

confidence: 95%

Utility of experimental animal models of myasthenia gravis for the elucidation of pathogenic mechanisms and development of new medications

Mori

Shigemoto

2019

Clinical & Exp Neuroim

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Myasthenia gravis (MG) is an autoimmune disease characterized by ptosis, fatigue and muscle weakness, caused by the association of pathogenic autoantibodies with postsynaptic membrane proteins at neuromuscular junctions. Although various autoantibodies have been found in sera from patients with MG, causal relationships with MG have not been shown for most antibodies. Establishment of the pathogenicity of candidate antibodies with experimental animal models of myasthenia gravis is indispensable. The pathogenicity of autoantibodies against acetylcholine receptors and musclespecific kinase has been confirmed by active immunization with purified antigens or by passive transfer of autoantibodies from patients with MG. Furthermore, animal models of MG have shown not only the pathogenic mechanisms underlying the manifestation of muscle weakness and atrophy observed in patients with MG, but also the efficacy of novel therapies and the adverse effects of therapeutic drugs. Here, we review the contributions of animal MG models to the elucidation of the pathogenic mechanisms of MG and the development of medications for the disease.

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“…An obvious strategy is to create deletion mutants of MuSK and quantify the interaction of these mutants with AChE/ColQ in vitro . This was done by Ohno and colleagues, who showed that, in vitro , AChE/ColQ binds to Ig1 and Ig4 (extracellular domain close to the transmembrane domain) in MuSK . However, according to the same group and using the same strategy, LRP4 also binds MuSK on the Ig1 and Ig4 domains.…”

Section: Perspectivesmentioning

confidence: 99%

Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms

Legay

2018

Annals of the New York Academy of Sciences

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The neuromuscular junction (NMJ) is a cholinergic synapse in vertebrates. This synapse connects motoneurons to muscles and is responsible for muscle contraction, a physiological process that is essential for survival. A key factor for the normal functioning of this synapse is the regulation of acetylcholine (ACh) levels in the synaptic cleft. This is ensured by acetylcholinesterase (AChE), which degrades ACh. A number of mutations in synaptic genes expressed in motoneurons or muscle cells have been identified and are causative for a class of neuromuscular diseases called congenital myasthenic syndromes (CMSs). One of these CMSs is due to deficiency in AChE, which is absent or diffuse in the synaptic cleft. Here, I focus on the origins of the syndrome. The role of ColQ, a collagen that anchors AChE in the synaptic cleft, is discussed in this context. Studies performed on patient biopsies, transgenic mice, and muscle cultures have provided a more comprehensive view of the connectome at the NMJ that should be useful for understanding the differences in the symptoms observed in specific CMSs due to mutated proteins in the synaptic cleft.

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Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling

Cited by 60 publications

References 60 publications

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

Utility of experimental animal models of myasthenia gravis for the elucidation of pathogenic mechanisms and development of new medications

Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms

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