Inhibition of synapse assembly in mammalian muscle <i>in vivo</i> by RNA interference

Kong, Xian; Barzaghi, Patrizia; Rüegg, Markus A.

doi:10.1038/sj.embor.7400065

Cited by 131 publications

(125 citation statements)

References 35 publications

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“…MuSK is essential for the development of the NMJ [51] but its role in adult muscle is less clear although it probably plays an important role in maintaining the structure of the postsynaptic membrane. [52] MuSK-MG often presents with ocular involvement, but frequently evolves to include severe bulbar and facial weakness, sometimes with marked muscle atrophy in these muscles. [53,54] Antibodies to MuSK [55] were demonstrated in around 70% of patients without AChR antibodies, and in none of the AChR antibody positive patients.…”

Section: Myasthenia Gravis With Muscle-speciþ C Kinase Antibodiesmentioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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The neuromuscular junction (NMJ) is a prototypic synapse although its structure is rather different from those of the central nervous system (CNS). The unmyelinated motor nerve terminals are separated from the postsynaptic membrane by a cleft that contains a basal lamina. This includes many proteins such as collagens, laminins, fibronectin and perlecan which help anchor some of the key elements involved in NMJ The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-speciÞ c kinase antibodies which deÞ ne a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immunemediated disorders of the NMJ.Key words: Gravis, Lambert Eaton myasthenic syndrome, neuromyotonia, neuromuscular junction, autoimmunity, acetylcholine receptor, voltage-gated channel development and function; for instance acetylcholine esterase (AChE) is localized via ColQ, a collagen-like molecule, to the basal lamina. Agrin and neuregulins, secreted from the nerve terminal, are bound by the basal lamina and interact with their receptors, playing an important role in the location of postsynaptic membrane proteins, voltage-gated calcium channels and the dystroglycans. The postsynaptic membrane at the NMJ forms a series of deep folds. The acetylcholine receptors (AChRs) are found at the top one-third of these folds, whereas the voltage-gated sodium channels are anchored at the bottom of the folds. The development of the NMJ is a fascinating area of research [1] and many of the proteins involved are relevant to disease ([ Figure 1] for a simple representation).The nerve action potential opens voltage-gated calcium channels (VGCCs) that are located in the motor nerve terminal [ Figure 1]. The resulting influx of calcium leads to the release of about 30 (in human muscle) individual packets of acetylcholine (ACh). Some of the ACh is hydrolysed by AChE but about 65%...

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Section: Myasthenia Gravis With Muscle-speciþ C Kinase Antibodiesmentioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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“…Notably, low levels of expression do not preclude that MuSK is functionally relevant. In fact, even in adult muscle, in which MuSK plays a critical role at the NMJ (Kong et al, 2004;Hesser et al, 2006), neither the mRNA nor the protein has yet been detected by Northern or Western blot analyses. Therefore, it is likewise possible that, despite low levels of expression, MuSK plays a significant function in several adult tissues and structures, including the brain.…”

Section: Musk Is Expressed In the Brain As Well As In Non-neuronal Timentioning

confidence: 99%

MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

et al. 2006

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Muscle-specific tyrosine kinase receptor (MuSK) has been believed to be mainly expressed and functional in muscle, in which it mediates the formation of neuromuscular junctions. Here we show that MuSK is expressed in the brain, particularly in neurons, as well as in non-neuronal tissues. We also provide evidence that MuSK expression in the hippocampus is required for memory consolidation, because temporally restricted knockdown after training impairs memory retention. Hippocampal disruption of MuSK also prevents the learning-dependent induction of both cAMP response element binding protein (CREB) phosphorylation and CCAAT enhancer binding protein ␤ (C/EBP␤) expression, suggesting that the role of MuSK during memory consolidation critically involves the CREB-C/EBP pathway. Furthermore, we found that MuSK also plays an important role in mediating hippocampal oscillatory activity in the theta frequency as well as in the induction and maintenance of long-term potentiation, two synaptic responses that correlate with memory formation. We conclude that MuSK plays an important role in brain functions, including memory formation. Therefore, its expression and role are broader than what was believed previously.

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“…MuSK regulates presynaptic differentiation, at least in part, by clustering Lrp4 in muscle, which functions bidirectionally by serving not only as a receptor for Agrin and as a ligand for MuSK but also as a direct retrograde signal for presynaptic differentiation (25). In addition to its role during synapse formation, MuSK is also required to maintain adult synapses, because inhibition of MuSK expression in adult muscle leads to profound defects in presynaptic and postsynaptic differentiation (26,27).…”

Section: Significancementioning

confidence: 99%

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Huijbers¹,

Zhang

Klooster³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

207

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Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii)

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Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference

Cited by 131 publications

References 35 publications

Autoimmune disorders of the neuromuscular junction

Autoimmune disorders of the neuromuscular junction

MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

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