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Neuromuscular junction proteines

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https://www.readbyqxmd.com/read/28635376/advances-in-understanding-the-role-of-disease-associated-proteins-in-spinal-muscular-atrophy
#1
Seyyedmohsen Hosseinibarkooie, Svenja Schneider, Brunhilde Wirth
Spinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by alpha motor neuron loss in the spinal cord due to reduced survival of motor neuron (SMN) protein level. While the genetic basis of SMA is well described, the specific molecular pathway underlying SMA is still not fully understood. Areas covered: This review discusses the recent advancements in understanding the molecular pathways in SMA using different omics approaches and genetic modifiers identified in both vertebrate and invertebrate systems...
June 21, 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28620838/modelling-fus-mislocalisation-in-an-in-vitro-model-of-innervated-human-muscle
#2
Sonja Prpar Mihevc, Mojca Pavlin, Simona Darovic, Marko Živin, Matej Podbregar, Boris Rogelj, Tomaz Mars
Degeneration of distal axons and neuromuscular junctions is an early feature in the pathology of amyotrophic lateral sclerosis (ALS), which culminates in motor neuron loss due to axon retraction and muscle atrophy. The complex interactions in the pathogenesis of ALS between motor neurons, muscle cells and accompanying glia require an appropriate experimental model. Here, we have defined a co-culture model based on human myotubes innervated by neurons from embryonic rat spinal cord explants to investigate the pathology and treatment of ALS...
June 15, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28603484/evolutionary-divergence-of-the-c-terminal-domain-of-complexin-accounts-for-functional-disparities-between-vertebrate-and-invertebrate-complexins
#3
Rachel T Wragg, Daniel A Parisotto, Zhenlong Li, Mayu S Terakawa, David Snead, Ishani Basu, Harel Weinstein, David Eliezer, Jeremy S Dittman
Complexin is a critical presynaptic protein that regulates both spontaneous and calcium-triggered neurotransmitter release in all synapses. Although the SNARE-binding central helix of complexin is highly conserved and required for all known complexin functions, the remainder of the protein has profoundly diverged across the animal kingdom. Striking disparities in complexin inhibitory activity are observed between vertebrate and invertebrate complexins but little is known about the source of these differences or their relevance to the underlying mechanism of complexin regulation...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28572757/muscle-contraction-regulates-bdnf-trkb-signaling-to-modulate-synaptic-function-through-presynaptic-cpkc%C3%AE-and-cpkc%C3%AE-i
#4
Erica Hurtado, Víctor Cilleros, Laura Nadal, Anna Simó, Teresa Obis, Neus Garcia, Manel M Santafé, Marta Tomàs, Katherine Halievski, Cynthia L Jordan, Maria A Lanuza, Josep Tomàs
The neurotrophin brain-derived neurotrophic factor (BDNF) acts via tropomyosin-related kinase B receptor (TrkB) to regulate synapse maintenance and function in the neuromuscular system. The potentiation of acetylcholine (ACh) release by BDNF requires TrkB phosphorylation and Protein Kinase C (PKC) activation. BDNF is secreted in an activity-dependent manner but it is not known if pre- and/or postsynaptic activities enhance BDNF expression in vivo at the neuromuscular junction (NMJ). Here, we investigated whether nerve and muscle cell activities regulate presynaptic conventional PKC (cPKCα and βI) via BDNF/TrkB signaling to modulate synaptic strength at the NMJ...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28556834/developmental-regulation-of-smn-expression-pathophysiological-implications-and-perspectives-for-therapy-development-in-spinal-muscular-atrophy
#5
REVIEW
S Jablonka, M Sendtner
Spinal muscular atrophy (SMA), the predominant form of motoneuron diease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction...
May 30, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28550099/viral-delivery-of-c9orf72-hexanucleotide-repeat-expansions-in-mice-lead-to-repeat-length-dependent-neuropathology-and-behavioral-deficits
#6
Saul Herranz-Martin, Jayanth Chandran, Katherine Lewis, Padraig Mulcahy, Adrian Higginbottom, Callum Walker, Isabel Martinez-Pena Y Valenzuela, Ross A Jones, Ian Coldicott, Tommaso Iannitti, Mohammed Akaaboune, Sherif F El-Khamisy, Thomas H Gillingwater, Pamela J Shaw, Mimoun Azzouz
Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28543723/neuromuscular-junctions-nmjs-ultrastructural-analysis-and-nicotinic-acetylcholine-receptor-nachr-subunit-mrna-expression-in-offspring-subjected-to-protein-restriction-throughout-pregnancy
#7
Paula Aiello Tomé de Souza Castro, Ludimila Canuto Faccioni, Patrícia Aline Boer, Robson Francisco Carvalho, Selma Maria Michelin Matheus, Maeli Dal-Pai-Silva
Protein restriction during gestation can alter the skeletal muscle phenotype of offspring; however, little is known with regard to whether this also affects the neuromuscular junction (NMJ), as muscle phenotype maintenance depends upon NMJ functional integrity. This study aimed to evaluate the effects of a low protein (6%) intake by dams throughout gestation on male offspring NMJ morphology and nicotinic acetylcholine receptor (nAChR) α1, γ and ε subunit expression in the soleus (SOL) and extensor digitorum longus (EDL) muscles...
May 25, 2017: International Journal of Experimental Pathology
https://www.readbyqxmd.com/read/28534855/rbc-adherence-of-immune-complexes-containing-botulinum-toxin-improves-neutralization-and-macrophage-uptake
#8
Fetweh H Al-Saleem, Rashmi Sharma, Rama Devudu Puligedda, Md Elias, Chandana Devi Kattala, Paul M Simon, Lance L Simpson, Scott K Dessain
In the paralytic disease botulism, the botulinum neurotoxin (BoNT) passes through the bloodstream to reach and inactivate neuromuscular junctions. Monoclonal antibodies (mAbs) may be useful BoNT countermeasures, as mAb combinations can rapidly clear BoNT from the blood circulation. We have previously shown that the BoNT-neutralizing potency of mAbs can be improved through red blood cell (RBC) immunoadherence. For example, a fusion protein (FP) that adheres biotinylated mAbs to the RBC surface enabled a pair of mAbs to neutralize 5000 LD50 BoNT/A in the mouse protection assay...
May 19, 2017: Toxins
https://www.readbyqxmd.com/read/28533206/myostatin-like-proteins-regulate-synaptic-function-and-neuronal-morphology
#9
Hrvoje Augustin, Kieran McGourty, Joern R Steinert, Helena M Cochemé, Jennifer Adcott, Melissa Cabecinha, Alec Vincent, Els F Halff, Josef T Kittler, Emmanuel Boucrot, Linda Partridge
Growth factors of the TGF-β superfamily play key roles in regulating neuronal and muscle function. Myostatin (or GDF8) and GDF11 are potent negative regulators of skeletal muscle mass. However, expression of both Myostatin and its cognate receptors in other tissues, including brain and peripheral nerves, suggests a potential wider biological role. Here, we show that Myoglianin (MYO), the Drosophila homolog of Myostatin and GDF11, regulates not only body weight and muscle size, but also inhibits neuromuscular synapse strength and composition in a Smad2-dependent manner...
May 22, 2017: Development
https://www.readbyqxmd.com/read/28520784/presynaptic-a%C3%AE-40-prevents-synapse-addition-in-the-adult-drosophila-neuromuscular-junction
#10
Begoña López-Arias, Enrique Turiégano, Ignacio Monedero, Inmaculada Canal, Laura Torroja
Complexity in the processing of the Amyloid Precursor Protein, which generates a mixture of βamyloid peptides, lies beneath the difficulty in understanding the etiology of Alzheimer's disease. Moreover, whether Aβ peptides have any physiological role in neurons is an unresolved question. By expressing single, defined Aβ peptides in Drosophila, specific effects can be discriminated in vivo. Here, we show that in the adult neuromuscular junction (NMJ), presynaptic expression of Aβ40 hinders the synaptic addition that normally occurs in adults, yielding NMJs with an invariable number of active zones at all ages tested...
2017: PloS One
https://www.readbyqxmd.com/read/28515212/regulation-of-wnt-signaling-at-the-neuromuscular-junction-by-the-immunoglobulin-super-family-protein-rig-3-in-caenorhabditis-elegans
#11
Pratima Pandey, Ashwani Bhardwaj, Kavita Babu
Perturbations in synaptic function could affect the normal behavior of an animal, making it important to understand the regulatory mechanisms of synaptic signaling. Previous work has shown that in Caenorhabditis elegans an immunoglobulin super-family protein, RIG-3, functions in pre-synaptic neurons to maintain normal acetylcholine receptor levels at the neuromuscular junction (NMJ). In this study we elucidate the molecular and functional mechanism of RIG-3. We demonstrate by genetic and BiFC (Bi-molecular Fluorescence Complementation) assays that pre-synaptic RIG-3 functions by directly interacting with the immunoglobulin domain of the non-conventional Wnt receptor, ROR receptor tyrosine kinase (RTK), CAM-1, that functions in post-synaptic body-wall muscles...
May 17, 2017: Genetics
https://www.readbyqxmd.com/read/28500055/rnai-mediated-reverse-genetic-screen-identified-drosophila-chaperones-regulating-eye-and-neuromuscular-junction-morphology
#12
Sandeep Raut, Bhagaban Mallik, Arpan Parichha, Amrutha V, Chandan Sahi, Vimlesh Kumar
Accumulation of toxic proteins in neurons have been linked with the onset of neurodegenerative diseases, which in many cases, are characterized by altered neuronal function and synapse loss. Molecular chaperones help protein folding and resolubilization of unfolded proteins thereby reducing the protein aggregation stress. While most of the chaperones are expressed in neurons, their functional relevance largely remains unknown. Here, using bioinformatics analysis, we identified 95 Drosophila chaperones and classified them into seven different classes...
May 12, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28490573/dok7-gene-therapy-enhances-motor-activity-and-life-span-in-als-model-mice
#13
Sadanori Miyoshi, Tohru Tezuka, Sumimasa Arimura, Taro Tomono, Takashi Okada, Yuji Yamanashi
Amyotrophic lateral sclerosis (ALS) is a progressive, multifactorial motor neurodegenerative disease with severe muscle atrophy. The glutamate release inhibitor riluzole is the only medication approved by the FDA, and prolongs patient life span by a few months, testifying to a strong need for new treatment strategies. In ALS, motor neuron degeneration first becomes evident at the motor nerve terminals in neuromuscular junctions (NMJs), the cholinergic synapse between motor neuron and skeletal muscle; degeneration then progresses proximally, implicating the NMJ as a therapeutic target...
May 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28489965/evidence-for-the-subsynaptic-zone-as-a-preferential-site-for-chrn-recycling-at-neuromuscular-junctions
#14
Franziska Wild, Muzamil Majid Khan, Rüdiger Rudolf
Vertebrate skeletal muscle contraction is mediated by nicotinic acetylcholine receptors (CHRN). Endocytosis and recycling of CHRN regulate their proper abundance at nerve-muscle synapses, i.e. neuromuscular junctions. Recent work showed that RAB5 is essential for CHRN endocytosis. Here, using in vivo-imaging of endocytosed CHRN and RAB-GFP fusion proteins, we deliver evidence for differential effects of RAB5-GFP, RAB4-GFP, and RAB11-GFP on CHRN endocytosis. Furthermore, while newly endocytosed CHRN colocalized with RAB5-GFP over large stretches of muscle fibers, RAB4-GFP and RAB11-GFP colocalized with endocytosed CHRN almost exclusively at neuromuscular junctions...
May 10, 2017: Small GTPases
https://www.readbyqxmd.com/read/28489002/usp5-leon-deubiquitinase-confines-postsynaptic-growth-by-maintaining-ubiquitin-homeostasis-through-ubiquilin
#15
Chien-Hsiang Wang, Yi-Chun Huang, Pei-Yi Chen, Ying-Ju Cheng, Hsiu-Hua Kao, Haiwei Pi, Cheng-Ting Chien
Synapse formation and growth are tightly controlled processes. How synaptic growth is terminated after reaching proper size remains unclear. Here, we show that Leon, the Drosophila USP5 deubiquitinase, controls postsynaptic growth. In leon mutants, postsynaptic specializations of neuromuscular junctions are dramatically expanded, including the subsynaptic reticulum, the postsynaptic density, and the glutamate receptor cluster. Expansion of these postsynaptic features is caused by a disruption of ubiquitin homeostasis with accumulation of free ubiquitin chains and ubiquitinated substrates in the leon mutant...
May 10, 2017: ELife
https://www.readbyqxmd.com/read/28488683/progressive-hereditary-spastic-paraplegia-caused-by-a-homozygous-ky-mutation
#16
Yuval Yogev, Yonatan Perez, Iris Noyman, Anwar Abu Madegem, Hagit Flusser, Zamir Shorer, Eugene Cohen, Leonid Kachko, Analia Michaelovsky, Ruth Birk, Arie Koifman, Max Drabkin, Ohad Wormser, Daniel Halperin, Rotem Kadir, Ohad S Birk
Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers...
May 10, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28488382/neuron-specific-knockdown-of-the-drosophila-fat-induces-reduction-of-life-span-deficient-locomotive-ability-shortening-of-motoneuron-terminal-branches-and-defects-in-axonal-targeting
#17
Aya Nakamura, Ryo Tanaka, Kazushige Morishita, Hideki Yoshida, Yujiro Higuchi, Hiroshi Takashima, Masamitsu Yamaguchi
Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system...
May 9, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28472174/augmented-quantal-release-of-acetylcholine-at-the-vertebrate-neuromuscular-junction-following-tdp-43-depletion
#18
Stefania Dzieciolowska, Pierre Drapeau, Gary Alan Barclay Armstrong
TAR DNA binding protein (TDP-43) is a 43 kD, predominately nuclear, protein involved in RNA metabolism. Of clinical significance is that the majority of amyotrophic lateral sclerosis (ALS) patients display abnormal accumulation of misfolded TDP-43 in the cytoplasm, which is coincident with a loss of nuclear localization in the afflicted regions of the central nervous system. Little is known about defects that arise in loss-of-function models, in particular synaptic defects that arise at the neuromuscular junction (NMJ)...
2017: PloS One
https://www.readbyqxmd.com/read/28470860/multiple-antibody-detection-in-seronegative-myasthenia-gravis-patients
#19
Y Hong, P Zisimopoulou, N Trakas, K Karagiorgou, C Stergiou, G O Skeie, H-J Hao, X Gao, J F Owe, X Zhang, Y-X Yue, F Romi, Q Wang, H-F Li, N E Gilhus, S J Tzartos
BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disease caused by antibody mediated impairment in the neuromuscular junction. Seronegative MG (SNMG) without antibodies against acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) by routine assays accounts for about 20% of all MG patients. METHODS: Plasma from 81 Chinese MG patients previously found to be seronegative was tested by routine assays for AChR and MuSK antibodies. These samples were screened by (i) a novel, highly sensitive radioimmunoassay for AChR antibodies; (ii) cell-based assays for clustered AChR, MuSK and lipoprotein receptor-related protein 4 (LRP4) antibodies; (iii) a radioimmunoassay for titin antibodies...
June 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28463115/decreased-microrna-levels-lead-to-deleterious-increases-in-neuronal-m2-muscarinic-receptors-in-spinal-muscular-atrophy-models
#20
Patrick J O'Hern, Inês do Carmo G Gonçalves, Johanna Brecht, Eduardo Javier López Soto, Jonah Simon, Natalie Chapkis, Diane Lipscombe, Min Jeong Kye, Anne C Hart
Spinal Muscular Atrophy (SMA) is caused by diminished Survival of Motor Neuron (SMN) protein, leading to neuromuscular junction (NMJ) dysfunction and spinal motor neuron (MN) loss. Here, we report that reduced SMN function impacts the action of a pertinent microRNA and its mRNA target in MNs. Loss of the C. elegans SMN ortholog, SMN-1, causes NMJ defects. We found that increased levels of the C. elegans Gemin3 ortholog, MEL-46, ameliorates these defects. Increased MEL-46 levels also restored perturbed microRNA (miR-2) function in smn-1(lf) animals...
May 2, 2017: ELife
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