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https://www.readbyqxmd.com/read/28441759/synaptic-homeostasis-and-its-immunological-disturbance-in-neuromuscular-junction-disorders
#1
REVIEW
Masaharu Takamori
In the neuromuscular junction, postsynaptic nicotinic acetylcholine receptor (nAChR) clustering, trans-synaptic communication and synaptic stabilization are modulated by the molecular mechanisms underlying synaptic plasticity. The synaptic functions are based presynaptically on the active zone architecture, synaptic vesicle proteins, Ca(2+) channels and synaptic vesicle recycling. Postsynaptically, they are based on rapsyn-anchored nAChR clusters, localized sensitivity to ACh, and synaptic stabilization via linkage to the extracellular matrix so as to be precisely opposed to the nerve terminal...
April 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28440223/structural-insights-into-the-molecular-mechanisms-of-myasthenia-gravis-and-their-therapeutic-implications
#2
Kaori Noridomi, Go Watanabe, Melissa N Hansen, Gye Won Han, Lin Chen
The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1...
April 25, 2017: ELife
https://www.readbyqxmd.com/read/28428759/morphological-regeneration-and-functional-recovery-of-neuromuscular-junctions-after-tourniquet-induced-injuries-in-mouse-hindlimb
#3
Huiyin Tu, Dongze Zhang, Ryan M Corrick, Robert L Muelleman, Michael C Wadman, Yu-Long Li
Tourniquet application and its subsequent release cause serious injuries to the skeletal muscle, nerve, and neuromuscular junction (NMJ) due to mechanical compression and ischemia-reperfusion (IR). Monitoring structural and functional repair of the NMJ, nerve, and skeletal muscle after tourniquet-induced injuries is beneficial in exploring potential cellular and molecular mechanisms responsible for tourniquet-induced injuries, and for establishing effective therapeutic interventions. Here, we observed long-term morphological and functional changes of the NMJ in a murine model of tourniquet-induced hindlimb injuries...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28422078/antivenom-for-neuromuscular-paralysis-resulting-from-snake-envenoming
#4
REVIEW
Anjana Silva, Wayne C Hodgson, Geoffrey K Isbister
Antivenom therapy is currently the standard practice for treating neuromuscular dysfunction in snake envenoming. We reviewed the clinical and experimental evidence-base for the efficacy and effectiveness of antivenom in snakebite neurotoxicity. The main site of snake neurotoxins is the neuromuscular junction, and the majority are either: (1) pre-synaptic neurotoxins irreversibly damaging the presynaptic terminal; or (2) post-synaptic neurotoxins that bind to the nicotinic acetylcholine receptor. Pre-clinical tests of antivenom efficacy for neurotoxicity include rodent lethality tests, which are problematic, and in vitro pharmacological tests such as nerve-muscle preparation studies, that appear to provide more clinically meaningful information...
April 19, 2017: Toxins
https://www.readbyqxmd.com/read/28326549/the-three-finger-toxin-fold-a-multifunctional-structural-scaffold-able-to-modulate-cholinergic-functions
#5
REVIEW
Pascal Kessler, Pascale Marchot, Marcela Silva, Denis Servent
Three-finger fold toxins are miniproteins frequently found in Elapidae snake venoms. This fold is characterized by three distinct loops rich in β-strands and emerging from a dense, globular core reticulated by four highly conserved disulfide bridges. The number and diversity of receptors, channels, and enzymes identified as targets of three-finger fold toxins is increasing continuously. Such manifold diversity highlights the specific adaptability of this fold for generating pleiotropic functions. Although this toxin superfamily disturbs many biological functions by interacting with a large diversity of molecular targets, the most significant target is the cholinergic system...
March 21, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28273388/enhanced-transport-of-plant-produced-rabies-single-chain-antibody-rvg-peptide-fusion-protein-across-an-in-cellulo-blood-brain-barrier-device
#6
Waranyoo Phoolcharoen, Christophe Prehaud, Craig J van Dolleweerd, Leonard Both, Anaelle da Costa, Monique Lafon, Julian K-C Ma
The biomedical applications of antibody engineering are developing rapidly and have been expanded to plant expression platforms. In this study, we have generated a novel antibody molecule in planta for targeted delivery across the blood-brain barrier (BBB). Rabies virus (RABV) is a neurotropic virus for which there is no effective treatment after entry into the central nervous system. This study investigated the use of a RABV glycoprotein peptide sequence to assist delivery of a rabies neutralizing single-chain antibody (ScFv) across an in cellulo model of human BBB...
March 8, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28238572/seronegative-myasthenia-gravis-associated-with-malignant-thymoma
#7
Jason Richards, James F Howard
Myasthenia gravis (MG) is generally caused by antibodies directed against the neuromuscular junction, including antibodies against the postsynaptic nicotinic acetylcholine receptor (AChR). Pathologic abnormalities of the thymus gland, including thymoma, are associated with MG. We report a 56-year-old woman who presented with double vision. Single fiber EMG confirmed myasthenia gravis. AChR, striational muscle and MuSK antibodies were absent in the serum. Chest CT demonstrated a malignant thymoma. We report the first case of seronegative myasthenia gravis associated with malignant thymoma...
May 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28209997/antisense-mir-132-blockade-via-the-ache-r-splice-variant-mitigates-cortical-inflammation
#8
Nibha Mishra, Lyndon Friedson, Geula Hanin, Uriya Bekenstein, Meshi Volovich, Estelle R Bennett, David S Greenberg, Hermona Soreq
MicroRNA (miR)-132 brain-to-body messages suppress inflammation by targeting acetylcholinesterase (AChE), but the target specificity of 3'-AChE splice variants and the signaling pathways involved remain unknown. Using surface plasmon resonance (SPR), we identified preferential miR-132 targeting of soluble AChE-R over synaptic-bound AChE-S, potentiating miR-132-mediated brain and body cholinergic suppression of pro-inflammatory cytokines. Inversely, bacterial lipopolysaccharide (LPS) reduced multiple miR-132 targets, suppressed AChE-S more than AChE-R and elevated inflammatory hallmarks...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28106831/ablation-of-protein-kinase-ck2%C3%AE-in-skeletal-muscle-fibers-interferes-with-their-oxidative-capacity
#9
Nane Eiber, Luca Simeone, Said Hashemolhosseini
The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be at least required for regular aggregation of nicotinic acetylcholine receptors, which serves as a hallmark for the presence of a postsynaptic apparatus. Here, we set out to determine whether any other feature accompanies CK2β-deficient muscle fibers...
January 19, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28088107/gaas-laser-therapy-reestablishes-the-morphology-of-the-nmj-and-nachrs-after-injury-due-to-bupivacaine
#10
Cristiane Neves Alessi Pissulin, Paula Aiello Tomé de Souza Castro, Flávio Codina, Carina Guidi Pinto, Ivan Jose Vechetti-Junior, Selma Maria Michelin Matheus
BACKGROUND: Local anesthetics are used to relieve pre- and postoperative pain, acting on both sodium channels and nicotinic acetylcholine receptors (nAChR) at the neuromuscular junction (NMJ). Bupivacaine acts as a non-competitive antagonist and has limitations, such as myotoxicity, neurotoxicity, and inflammation. Low-level laser therapy (LLLT) has anti-inflammatory, regenerative, and analgesic effects. The aim of the present study was to evaluate the effects of a gallium arsenide laser (GaAs) on the morphology of the NMJ and nAChRs after application of bupivacaine in the sternomastoid muscle...
February 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28018246/acetylcholine-induced-inhibition-of-presynaptic-calcium-signals-and-transmitter-release-in-the-frog-neuromuscular-junction
#11
Eduard Khaziev, Dmitry Samigullin, Nikita Zhilyakov, Nijaz Fatikhov, Ellya Bukharaeva, Alexei Verkhratsky, Evgeny Nikolsky
Acetylcholine (ACh), released from axonal terminals of motor neurons in neuromuscular junctions regulates the efficacy of neurotransmission through activation of presynaptic nicotinic and muscarinic autoreceptors. Receptor-mediated presynaptic regulation could reflect either direct action on exocytotic machinery or modulation of Ca(2+) entry and resulting intra-terminal Ca(2+) dynamics. We have measured free intra-terminal cytosolic Ca(2+) ([Ca(2+)]i) using Oregon-Green 488 microfluorimetry, in parallel with voltage-clamp recordings of spontaneous (mEPC) and evoked (EPC) postsynaptic currents in post-junctional skeletal muscle fiber...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27715385/progress-of-endocytic-chrn-to-autophagic-degradation-is-regulated-by-rab5-gtpase-and-t145-phosphorylation-of-sh3glb1-at-mouse-neuromuscular-junctions-in-vivo
#12
Franziska Wild, Muzamil Majid Khan, Tatjana Straka, Rüdiger Rudolf
Endocytosed nicotinic acetylcholine receptors (CHRN) are degraded via macroautophagy/autophagy during atrophic conditions and are accompanied by the autophagic regulator protein SH3GLB1. The present study addressed the functional role of SH3GLB1 on CHRN trafficking and its implementation. We found an augmented ratio of total SH3GLB1 to threonine-145 phosphorylated SH3GLB1 (SH3GLB1:p-SH3GLB1) under conditions of increased CHRN vesicle numbers. Overexpression of T145 phosphomimetic (T145E) and phosphodeficient (T145A) mutants of SH3GLB1, was found to either slow down or augment the processing of endocytic CHRN vesicles, respectively...
December 2016: Autophagy
https://www.readbyqxmd.com/read/27705071/sarin-gb-o-isopropyl-methylphosphonofluoridate-neurotoxicity-critical-review
#13
Mohamed B Abou-Donia, Briana Siracuse, Natasha Gupta, Ashly Sobel Sokol
Sarin (GB, O-isopropyl methylphosphonofluoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as "cholinergic crisis" (i...
November 2016: Critical Reviews in Toxicology
https://www.readbyqxmd.com/read/27698745/concomitant-presentation-of-anderson-tawil-syndrome-and-myasthenia-gravis-in-an-adult-patient-a-case-report
#14
Rui Fan, Ruirui Ji, Wenxin Zou, Guoliang Wang, Hu Wang, Daniel James Penney, Jin Jun Luo, Yuxin Fan
Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies...
October 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27698419/x-ray-structure-of-the-human-%C3%AE-4%C3%AE-2-nicotinic-receptor
#15
Claudio L Morales-Perez, Colleen M Noviello, Ryan E Hibbs
Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have diverse signalling roles in the central nervous system. The nicotinic receptor has been a model system for cell-surface receptors, and specifically for ligand-gated ion channels, for well over a century. In addition to the receptors' prominent roles in the development of the fields of pharmacology and neurobiology, nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery...
October 20, 2016: Nature
https://www.readbyqxmd.com/read/27677608/a-novel-fusion-protein-achr-fc-ameliorates-myasthenia-gravis-by-neutralizing-antiacetylcholine-receptor-antibodies-and-suppressing-acetylcholine-receptor-reactive-b-cells
#16
Masayuki Homma, Akiyuki Uzawa, Hitoshi Tanaka, Naoki Kawaguchi, Tetsuya Kanai, Kenji Nakajima, Masakuni Narita, Yukio Hara, Hideya Maruyama, Yasumasa Ogawa, Keiichi Himuro, Satoshi Kuwabara
Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which leads to muscle weakness. We developed a fusion protein, AChR-Fc, as a novel therapeutic biomolecule for patients with MG and examined its efficacy. AChR-Fc was expressed by Chinese hamster ovary cells and purified. We examined the neutralizing activity and cellular cytotoxicity of AChR-Fc using anti-AChR antibody-producing hybridoma cells and serum samples from 16 patients with MG...
January 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/27669271/acetamiprid-accumulates-in-different-amounts-in-murine-brain-regions
#17
Hayato Terayama, Hitoshi Endo, Hideo Tsukamoto, Koichi Matsumoto, Mai Umezu, Teruhisa Kanazawa, Masatoshi Ito, Tadayuki Sato, Munekazu Naito, Satoshi Kawakami, Yasuhiro Fujino, Masayuki Tatemichi, Kou Sakabe
Neonicotinoids such as acetamiprid (ACE) belong to a new and widely used single class of pesticides. Neonicotinoids mimic the chemical structure of nicotine and share agonist activity with the nicotine acetylcholine receptor (nAchR). Neonicotinoids are widely considered to be safe in humans; however, they have recently been implicated in a number of human health disorders. A wide range of musculoskeletal and neuromuscular disorders associated with high doses of neonicotinoids administered to animals have also been reported...
September 22, 2016: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/27585036/the-fibular-nerve-injury-method-a-reliable-assay-to-identify-and-test-factors-that-repair-neuromuscular-junctions
#18
William Dalkin, Thomas Taetzsch, Gregorio Valdez
The neuromuscular junction (NMJ) undergoes deleterious structural and functional changes as a result of aging, injury and disease. Thus, it is imperative to understand the cellular and molecular changes involved in maintaining and repairing NMJs. For this purpose, we have developed a method to reliably and consistently examine regenerating NMJs in mice. This nerve injury method involves crushing the common fibular nerve as it passes over the lateral head of the gastrocnemius muscle tendon near the knee. Using 70 day old female mice, we demonstrate that motor axons begin to reinnervate previous postsynaptic targets within 7 days post-crush...
2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27563924/the-dinoflagellate-toxin-20-methyl-spirolide-g-potently-blocks-skeletal-muscle-and-neuronal-nicotinic-acetylcholine-receptors
#19
Aurélie Couesnon, Rómulo Aráoz, Bogdan I Iorga, Evelyne Benoit, Morgane Reynaud, Denis Servent, Jordi Molgó
The cyclic imine toxin 20-methyl spirolide G (20-meSPX-G), produced by the toxigenic dinoflagellate Alexandrium ostenfeldii/Alexandrium peruvianum, has been previously reported to contaminate shellfish in various European coastal locations, as revealed by mouse toxicity bioassay. The aim of the present study was to determine its toxicological profile and its molecular target selectivity. 20-meSPX-G blocked nerve-evoked isometric contractions in isolated mouse neuromuscular preparations, while it had no action on contractions elicited by direct electrical stimulation, and reduced reversibly nerve-evoked compound muscle action potential amplitudes in anesthetized mice...
August 24, 2016: Toxins
https://www.readbyqxmd.com/read/27513355/neuromuscular-recovery-is-prolonged-after-immobilization-or-superimposition-of-inflammation-with-immobilization-compared-to-inflammation-alone-data-from-a-preclinical-model
#20
Christiane G Stäuble, Marc Helming, J A Jeevendra Martyn, Manfred Blobner, Heidrun Fink
OBJECTIVES: Recovery from ICU-acquired muscle weakness extends beyond hospital stay. We hypothesized that immobilization, more than inflammation, plays a prominent role in the delayed recovery from critical illness. DESIGN: Prospective, randomized, controlled, experimental study. SETTING: Animal laboratory, university hospital. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Animals were divided to have one hind limb immobilized (n = 129) or sham-immobilized (n = 129) on day -12...
November 2016: Critical Care Medicine
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