Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Formation of the skeletal neuromuscular junction is a multi-step process that requires communication between the nerve and muscle. Studies in many laboratories have led to identification of factors that seem likely to mediate these interactions. 'Knock-out' mice have now been generated with mutations in several genes that encode candidate transsynaptic messengers and components of their effector mechanisms. Using these mice, it is possible to test hypotheses about the control of synaptogenesis. Here, we review our studies on neuromuscular development in mutant mice lacking agrin alpha CGRP, rapsyn, MuSK, dystrophin, dystrobrevin, utrophin, laminin alpha 5, laminin beta 2, collagen alpha 3 (IV), the acetylcholine receptor epsilon subunit, the collagenous tail of acetylcholinesterase, fibroblast growth factor-5, the neural cell adhesion molecule, and tenascin-C.
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PMID:Development of the neuromuscular junction: genetic analysis in mice. 978 2

Serum antibodies to muscle-specific receptor tyrosine kinase were detected in 12 of 32 patients with generalized seronegative MG. All were women, with onset between ages 21 and 59 years. Seven had prominent neck, shoulder, or respiratory muscle weakness and little or delayed ocular muscle involvement. The response to cholinesterase inhibitors was variable, and electromyographic findings suggested myopathy in several. None improved after thymectomy. All patients improved after plasma exchange, and most had a good response to selected immunotherapy. MuSK antibody status should help diagnose MG with atypical presentations and ensure appropriate patient treatment.
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PMID:Clinical aspects of MuSK antibody positive seronegative MG. 1282 44

The autosomal recessive neuromuscular disorder associated with the enervated (enr) mouse transgene insertion manifests impaired peripheral nerve regeneration due to defects in Schwann cells and resembles the myodystrophy (Large(myd)) phenotype. Here we show that the enr transgene has integrated into Chr 8 approximately 160 kb downstream from the 3' end of the Large gene disrupting its expression as confirmed by the lack of genetic complementation between Large(myd) and enr mice, the very low Large mRNA levels in enr tissues and hypoglycosylation of alpha-dystroglycan, a known substrate of LARGE. Mutant nerve conduction and grip strength were impaired whereas sodium channel clustering at the nodes of Ranvier was unaffected. Interestingly, the mutant neuromuscular junctions displayed abnormal acetylcholine receptor clustering with reduced immunostaining for beta-dystroglycan, laminin, agrin, MuSK, and to a lesser extent acetylcholinesterase and rapsyn. These data implicate LARGE in nerve, muscle, and neuromuscular junction function.
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PMID:Disruption of the mouse Large gene in the enr and myd mutants results in nerve, muscle, and neuromuscular junction defects. 1579 22

Investigation of congenital myasthenic syndromes (CMSs) disclosed a diverse array of molecular targets at the motor endplate. Clinical, electrophysiologic and morphologic studies paved the way for detecting CMS-related mutations in proteins such as the acetylcholine receptor, acetylcholinesterase, choline acetyltransferase, rapsyn, MuSK and Na(v)1.4. Analysis of electrophysiologic and biochemical properties of mutant proteins expressed in heterologous systems contributed crucially to defining the molecular consequences of the observed mutations and resulted in improved therapy of different CMSs. Recent crystallography studies of choline acetyltransferase and homology structural models of the acetylcholine receptor are providing further clues to how point mutations alter protein function.
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PMID:Current understanding of congenital myasthenic syndromes. 1590 19

Two proteins, ColQ and PRiMA, organize tetramers of acetylcholinesterase (AChE) and of butyrylcholinesterase (BChE) through peptide interactions. A short proline rich sequence in the N-terminal domain of ColQ or PRiMA associates four C-terminal extension of AChE or BChE. ColQ targets the enzymes in the basal lamina, PRiMA targets the enzymes at the plasma membrane. These complexes represent the mature proteins. The unassembled C-terminal extention of AChE is the key determinant recognized during the "quality control" of protein synthesis. Unassembled catalytic subunits are then degraded by the proteasome pathway. At the neuromuscular junction, ColQ/AChE represents the concentrated enzyme. The clusterisation of AChE depends upon ColQ through three sites of interactions: two different heparin binding domains in the collagen domain interact with heparan sulfate proteoglycan particularly the perlecan and the C-terminal non collagenic domain interacts with MuSK, the tyrosine kinase receptor organiser of the neuromuscular junction. The absence of ColQ and AChE has revealed that the excess of Ach stimulates more nicotinic receptors but probably not until their desensitization. Several morphological modifications may help the clearance of Ach. Conversely the synapse transmission fails during high frequency nerve stimulation.
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PMID:[Cholinesterases: anchored enzymes in membranes and basal laminae]. 1611 64

The collagen-tailed form of acetylcholinesterase (ColQ-AChE) is the major if not unique form of the enzyme associated with the specialized synaptic basal lamina at the neuromuscular junction (NMJ). This enzyme form consists of both catalytic and non-catalytic subunits encoded by separate genes, assembled as three enzymatic tetramers attached to the three-stranded collagen-like tail. We have previously shown that catalytic subunits are assembled in the rough endoplasmic reticulum and that after approximately 90min a subset of these tetramers assemble with collagenic tail subunits in the Golgi apparatus. In muscle, blocking ER to Golgi transport with Brefeldin A prevents the appearance of ColQ-AChE, consistent with assembly of asymmetric forms in the Golgi. Moreover, newly synthesized and assembled ColQ-AChE associates with perlecan intracellularly and can only be co-immunoprecipitated with anti-perlecan antibodies 90min after the first appearance of catalytic subunits. Once assembled, the ColQ-AChE/perlecan complex is externalized where it co-localizes with other components of the NMJ including dystroglycan, rapsyn, laminin and MuSK. These clusters tend to form over the nuclei that are expressing the components, suggesting local vectorial transport to the cell surface, and may form a primary scaffold that in turn can capture other molecular constituents of the neuromuscular synapse. While most AChE clusters on quail myotubes are devoid of acetylcholine receptors, treatment of the culture with recombinant agrin results in a rapid translocation of receptors to the AChE clusters in less than 4h. It remains to be determined if MuSK is localized to the clusters. In vivo, AChE transcripts and enzyme are more highly expressed at the NMJs, implying higher rates of AChE translation and assembly in the synaptic regions, and hence more ColQ-AChE for localized export. We have previously shown that binding sites for ColQ-AChE are concentrated at sites of nerve-muscle contact where they colocalize with AChR and perlecan. ColQ-AChE binds directly to perlecan using solid phase microtiter plate assay, the Biacore assay, and co-immunoprecipitations. Moreover, perlecan binds to dystroglycan at the NMJ. In perlecan or dystroglycan null mice there is no accumulation of AChE at the NMJ, supporting the hypothesis that this heparan sulfate proteoglycan is an essential component of the ColQ-AChE localization mechanism. Together, these studies suggest a model of synaptic development whereby AChE can be targeted to and clustered on the muscle membrane together with dystroglycan and perlecan to form scaffolds to which AChR can be clustered through activation of the MuSK receptor. At mature synapses ColQ-AChE is secreted directly into the synaptic cleft where it binds to the heparan sulfate proteoglycan perlecan as well as potentially other molecules including MuSK, as was recently reported.
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PMID:Targeting acetylcholinesterase to the neuromuscular synapse. 1628 17

The efficiency and the tight control of neurotransmission require the accumulation of synaptic proteins in discrete domains. In neuromuscular junctions, the main form of acetylcholinesterase (AChE) is a hetero-oligomer in which the catalytic subunits are associated to a specific collagen, ColQ. This structural protein is responsible for the insertion and the accumulation of AChE in the synaptic basal lamina. We have analyzed the time-course of acetylcholinesterase and acetylcholine receptors (AChR) mRNAs during mouse muscle cell differentiation in culture. In parallel, we have visualized the formation of AChE and AChR aggregates. We show that AChR clusters form first which correlates with high gamma-subunit mRNA levels. Then, AChE clusters appear with the onset of contraction and correlate with a dramatic increase in AChE, ColQ1 and ColQ1A mRNA levels in muscle cells. At that stage, AChR gamma-subunit levels drop while the expression level of epsilon-subunits increase. AChE aggregates are organized by a ternary complex, which involves direct interactions between ColQ, perlecan and MuSK.
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PMID:Acetylcholinesterase and molecular interactions at the neuromuscular junction. 1628 1

The genes encoding several synaptic proteins, including acetylcholine receptors, acetylcholinesterase, and the muscle-specific kinase, MuSK, are expressed selectively by a small number of myofiber nuclei positioned near the synaptic site. Genetic analysis of mutant mice suggests that additional genes, expressed selectively by synaptic nuclei, might encode muscle-derived retrograde signals that regulate the differentiation of motor axon terminals. To identify candidate retrograde signals, we used a microarray screen to identify genes that are preferentially expressed in the synaptic region of muscle, and we analyzed one such gene, CD24, further. We show that CD24, which encodes a small, variably and highly glycosylated, glycosylphosphatidylinositol (GPI)-linked protein, is expressed preferentially by myofiber synaptic nuclei in embryonic and adult muscle, and that CD24 expression is restricted to the central region of muscle independent of innervation. Moreover, we show that CD24 has a role in presynaptic differentiation, because synaptic transmission is depressed and fails entirely, in a cyclical manner, after repetitive stimulation of motor axons in CD24 mutant mice. These deficits in synaptic transmission, which are accompanied by aberrant stimulus-dependent uptake of AM1-43 from axons, indicate that CD24 is required for normal presynaptic maturation and function. Because CD24 is also expressed in some neurons, additional experiments will be required to determine whether pre- or postsynaptic CD24 mediates these effects on presynaptic development and function.
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PMID:CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission. 1660 32

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission, usually recognized with ocular complaints or generalized muscle weakness. However, among the 1520 MG cases that had been diagnosed and treated in our hospital in the last 15 years (1990-2005), we have identified 7 MG patients whose initial and prominent complaint was dysphonia and all had been misdiagnosed elsewhere. The diagnoses were confirmed with fibrolaryngoscope and voice analysis employed before and after a positive neostigmine (anticholinesterase) test. Electromyography with repetitive stimulations, single-fiber electromyography, and laboratory and radiographic evaluations were also conducted for diagnosis. A surprisingly low seropositivity rate of anti-acetylcholine-receptor antibodies (1/7) and anti-MuSK (Muscle Specific Kinase) antibodies (0/6) were found in these dysphonia MG patients. A cholinesterase inhibitor (ChEI) and immunosuppressive therapy were applied for treatment. Extended thymectomy was applied to MG patients with thymus hyperplasia or thymic tumor. Significant improvement was found in all 7 cases after these treatments. We have developed a sere of diagnostic protocol for this rare type of laryngeal MG, and discussed the clinical implication of our data. In summary, dysphonia or laryngeal disorder can be the only prominent manifestation of MG in rare cases, which should be taken into consideration during the diagnosis to patients with exclusive laryngeal complaints.
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PMID:Dysphonia as a primary manifestation in myasthenia gravis (MG): a retrospective review of 7 cases among 1520 MG patients. 1746 37

The vertebrate neuromuscular junction (NMJ) is marked by molecular specializations that include postsynaptic clusters of acetylcholine receptor (AChR) and acetylcholinesterase (AChE). Whereas AChRs are aggregated in the postsynaptic muscle membrane to a density of 10,000/mum(2), AChE is concentrated, also to a high density, in the synaptic basement membrane (BM). In recent years considerable progress has been made in understanding the cellular and molecular mechanisms of AChR clustering. It is known that during the early stages of motoneuron-muscle interaction, the nerve-secreted proteoglycan agrin activates the muscle-specific kinase MuSK, which leads to the formation of a postsynaptic cytoskeletal scaffold that immobilizes and concentrates AChRs through a process generally accepted to involve diffusion-mediated trapping of the receptors. We have recently tested this diffusion-trap model at the single molecule level for the first time by using quantum-dot labeling to track individual AChRs during NMJ development. Our results showed that single AChRs exhibit Brownian-type movement, with diffusion coefficients of 10(-11) to 10(-9)cm(2)/s, until they become immobilized at "traps" assembled in response to synaptogenic stimuli. Thus, free diffusion of AChRs is an integral part of their clustering mechanism. What is the mechanism for AChE clustering? We previously showed that the A(12) asymmetric form of AChE binds to perlecan, a heparan-sulfate proteoglycan which in turn interacts with the transmembrane dystroglycan complex. Through this linkage AChE becomes bound to the muscle membrane and, like AChRs, may exhibit lateral mobility along the membrane. Consistent with this idea, pre-existent AChE at the cell surface becomes clustered together with AChRs following synaptogenic stimulation. Future studies testing diffusion-mediated trapping of AChE should provide insights into the synaptic localization of BM-bound molecules at the NMJ.
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PMID:Transmembrane mechanisms in the assembly of the postsynaptic apparatus at the neuromuscular junction. 1851 12


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