Article

Pre- and postsynaptic neuromuscular junction abnormalities in MuSK myasthenia

Department of Neurology, Leiden University Medical Center, K5Q-114, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Muscle & Nerve (Impact Factor: 2.31). 08/2010; 42(2). DOI: 10.1002/mus.21642
Source: OAI

ABSTRACT Autoantibodies to muscle-specific kinase (MuSK) can cause myasthenia gravis (MG). The pathophysiological mechanism remains unknown. We report in vitro electrophysiological and histological studies of the neuromuscular junction in a MuSK MG patient. Low levels of presynaptic acetylcholine release and small miniature endplate potentials were found. This combination of pre- and postsynaptic abnormalities was supported by histology, revealing partially denervated postsynaptic areas, and some degeneration of postsynaptic folds. Results suggest that anti-MuSK antibodies reduce the stability of muscle-nerve contact.

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    • "Jointly, the passive and active MuSK MG mouse models show that MuSK autoantibodies (of the IgG4 subclass) are severely pathogenic and cause reduced MEPP amplitude without compensatory increased ACh release, paralleled by low MEPP frequency and extra EPP rundown. These combined post-and presynaptic defects explain the (fatigable) muscle weakness, and have also been observed in the few human biopsy studies (Niks et al., 2010; Selcen et al., 2004), giving high clinical relevance to the MuSK MG mouse models. The models will be instrumental in further pathophysiological analysis as well as in drug studies. "
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    ABSTRACT: Study of the electrophysiological function of the neuromuscular junction (NMJ) is instrumental in the understanding of the symptoms and pathophysiology of myasthenia gravis (MG), an autoimmune disorder characterized by fluctuating and fatigable muscle weakness. Most patients have autoantibodies to the acetylcholine receptor at the NMJ. However, in recent years autoantibodies to other crucial postsynaptic membrane proteins have been found in previously 'seronegative' MG patients. Electromyographical recording of compound and single-fibre muscle action potentials provides a crucial in vivo method to determine neuromuscular transmission failure while ex vivo (miniature) endplate potential recordings can reveal the precise synaptic impairment. Here we will review these electrophysiological methods used to assess NMJ function and discuss their application and typical results found in the diagnostic and experimental study of patients and animal models of the several forms of MG. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 01/2015; 270. DOI:10.1016/j.expneurol.2015.01.007 · 4.62 Impact Factor
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    • "In recordings from muscles obtained from MuSK MG patients (Niks et al., 2010) and from mice immunized against MuSK (Viegas et al., 2012), mEPPs were found to be significantly reduced. However, in contrast to the NMJ studies in mice and human discussed above, there was no evidence of increased presynaptic release in MuSK-dependent MG, indicating a lack of homeostatic expression (Niks et al., 2010; Viegas et al., 2012). Compared to AChR-associated MG, MuSK-related MG is more severe, is treatment-resistant, and is observed more broadly in the musculature, affecting bulbar, facial, and respiratory muscles as well (Evoli et al., 2003), which is likely due, in part, to a lack of homeostatic compensation. "
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    ABSTRACT: Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.
    Frontiers in Cellular Neuroscience 11/2013; 7:223. DOI:10.3389/fncel.2013.00223 · 4.18 Impact Factor
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    • "with the decreased SSC amplitude in the NMJ, suggesting a defect in ACh release upregulation which may reflect retrograde Wnt signaling at the nerve terminal (Luo et al., 2002). The antibody-induced disturbance in bidirectional Wnt signaling via MuSK may, at least in part, be compatible with presynaptic abnormalities including the absence of ACh release upregulation to compensate for postsynaptic failure found in anti-MuSK-positive MG patients (Niks et al., 2010) and animal models (Cole et al., 2008; Richman et al., 2011; Klooster et al., 2012; Mori et al., 2012; Viegas et al., 2012). We demonstrated that MuSK antibodies have heterogeneity in their binding to functional domains of MuSK. "
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    ABSTRACT: Muscle-specific tyrosine kinase (MuSK) antibodies are detected in a proportion of myasthenia gravis (MG) patients who are negative for acetylcholine receptor (AChR) antibodies and have prominent bulbar weakness and crises. In the MuSK ectodomains, the immunoglobulin-like 1 and 2 domains (Ig1/2) mediate the agrin–Lrp4–MuSK signaling and the cysteine-rich domain (CRD) mediates the Wnt–MuSK–Dishevelled signaling; both contribute to AChR clustering. Immunoblotting against recombinant proteins showed MuSK Ig1/2 antibodies in 33 anti-AChR-negative MG patients; 10 patients of them (30%) were additionally positive for MuSK CRD antibodies. The result suggests that MuSK antibodies have heterogeneity in their binding to functional domains of MuSK.
    Journal of neuroimmunology 01/2013; 254(s 1–2):183–186. DOI:10.1016/j.jneuroim.2012.09.001 · 2.79 Impact Factor
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Erik H Niks