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Hiroshi Manya, Yoshiki Yamaguchi, Motoi Kanagawa, Kazuhiro Kobayashi, Michiko Tajiri, Keiko Akasaka-Manya, Hiroko Kawakami, Mamoru Mizuno, Yoshinao Wada, Tatsushi Toda, Tamao Endo
A defect in O-mannosyl glycan is the cause of α-dystroglycanopathy, a group of congenital muscular dystrophies caused by aberrant α-dystroglycan (α-DG) glycosylation. Recently, the entire structure of O-mannosyl glycan, [3GlcAβ1-3Xylα1]n-3GlcAβ1-4Xyl-Rbo5P-1Rbo5P-3GalNAcβ1-3GlcNAcβ1-4(phospho-6)Manα1-, which is required for the binding of α-DG to extracellular matrix ligands, has been proposed. However, the linkage of the first Xyl residue to ribitol-5-phosphate (Rbo5P) is not clear. TMEM5 is a gene product responsible for α-dystroglycanopathy and was reported as a potential enzyme involved in this linkage formation, although the experimental evidence is still incomplete...
October 12, 2016: Journal of Biological Chemistry
Anthony Blaeser, Hiroyuki Awano, Bo Wu, Qi-Long Lu
Mutations in the gene for fukutin-related protein represent a subset of muscular dystrophies known as dystroglycanopathies characterized by loss of functionally-glycosylated-alpha-dystroglycan and a wide range of dystrophic phenotypes. Mice generated by our lab containing the P448L mutation in the fukutin-related protein gene demonstrate the dystrophic phenotype similar to that of LGMD2I. Here we examined the morphology of the heart and diaphragm, focusing on pathology of diaphragm and cardiac function of the mutant mice for up to 12 months...
2016: PloS One
Simon Früh, Jennifer Romanos, Patrizia Panzanelli, Daniela Bürgisser, Shiva K Tyagarajan, Kevin P Campbell, Mirko Santello, Jean-Marc Fritschy
: Distinct types of GABAergic interneurons target different subcellular domains of pyramidal cells, thereby shaping pyramidal cell activity patterns. Whether the presynaptic heterogeneity of GABAergic innervation is mirrored by specific postsynaptic factors is largely unexplored. Here we show that dystroglycan, a protein responsible for the majority of congenital muscular dystrophies when dysfunctional, has a function at postsynaptic sites restricted to a subset of GABAergic interneurons...
October 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Gabriela A Altamirano, Jorge G Ramos, Ayelen L Gomez, Enrique H Luque, Monica Muñoz-de-Toro, Laura Kass
With the aim to analyze whether bisphenol A (BPA) modifies β-Casein (β-Cas) synthesis and transcriptional regulation in perinatally exposed animals, here, pregnant F0 rats were orally exposed to 0, 0.6 or 52 μg BPA/kg/day from gestation day 9 until weaning. Then, F1 females were bred and mammary glands were obtained on lactation day 2. Perinatal BPA exposure decreased β-Cas expression without modifying the activation of prolactin receptor. It also decreased the expression of glucocorticoid receptor in BPA52-exposed dams and β1 and α6 integrins as well as dystroglycan in both BPA groups...
September 30, 2016: Molecular and Cellular Endocrinology
Lia Millucci, Giulia Bernardini, Barbara Marzocchi, Daniela Braconi, Michela Geminiani, Silvia Gambassi, Marcella Laschi, Bruno Frediani, Federico Galvagni, Maurizio Orlandini, Annalisa Santucci
Alkaptonuria (AKU) is a rare genetic disease that affects the entire joint. Current standard of AKU treatment is palliative and little is known about its physiopathology. Neovascularization is involved in the pathogenesis of systemic inflammatory rheumatic diseases, a family of related disorders that includes AKU. Here, we investigated the presence of neoangiogenesis in AKU synovium and healthy controls. Synovium from AKU patients, who had undergone total joint replacement or arthroscopy, or from healthy patients without any history of rheumatic diseases, who underwent surgical operation following sport trauma was subjected to hematoxylin and eosin staining...
November 2016: Journal of Inherited Metabolic Disease
Ayako Uchinaka, Kanako Tasaka, Yoko Mizuno, Yoshitaka Maeno, Tsuyoshi Ban, Seiji Mori, Yoshinosuke Hamada, Shigeru Miyagawa, Atsuhiro Saito, Yoshiki Sawa, Nariaki Matsuura, Kohzo Nagata, Hirofumi Yamamoto, Naomasa Kawaguchi
OBJECTIVES: Skeletal myoblast sheet (SMB) transplantation, a method used for treating failing hearts, results in the secretion of cytokines that improve heart function. Enhancing the survival rate of implanted myoblasts should yield more continuous and effective therapies. We hypothesized that laminin-211 (merosin), a major component of skeletal muscle extracellular matrix (ECM), which mediates cell-to-ECM adhesion by binding to α-dystroglycan (αDG) on muscle cells, could inhibit detachment of implanted myoblasts from host myocardia...
September 23, 2016: European Journal of Cardio-thoracic Surgery
Shelly Th McClatchey, Zheng Wang, Lara M Linden, Eric L Hastie, Lin Wang, Wanqing Shen, Alan Chen, Qiuyi Chi, David R Sherwood
Epithelial cells and their underlying basement membranes (BMs) slide along each other to renew epithelia, shape organs, and enlarge BM openings. How BM sliding is controlled, however, is poorly understood. Using genetic and live cell imaging approaches during uterine-vulval attachment in C. elegans, we have discovered that the invasive uterine anchor cell activates Notch signaling in neighboring uterine cells at the boundary of the BM gap through which it invades to promote BM sliding. Through an RNAi screen, we found that Notch activation upregulates expression of ctg-1, which encodes a Sec14-GOLD protein, a member of the Sec14 phosphatidylinositol-transfer protein superfamily that is implicated in vesicle trafficking...
September 23, 2016: ELife
Q-Z Zhang
Dystroglycanopathies are muscular dystrophies caused by mutations in genes involved the in O-linked glycosylation of α-dystroglycan. Severe forms of these conditions result in abnormalities in exhibit brain and ocular developmental too, in addition to muscular dystrophy. The full spectrum of developmental pathology is caused mainly by loss of dystroglycan from Bergmann glia. Moreover, cognitive deficits are constant features of severe forms of dystroglycanopathies. However, the precise molecular mechanism leading to neuronal dysfunction in these diseases is not fully known yet...
September 2016: European Review for Medical and Pharmacological Sciences
Erik P Rader, Rolf Turk, Tobias Willer, Daniel Beltrán, Kei-Ichiro Inamori, Taylor A Peterson, Jeffrey Engle, Sally Prouty, Kiichiro Matsumura, Fumiaki Saito, Mary E Anderson, Kevin P Campbell
Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Robert S Rogers, Hiroshi Nishimune
The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and β2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones...
September 7, 2016: Matrix Biology: Journal of the International Society for Matrix Biology
Hadas Cohen-Dvashi, Hadar Israeli, Orly Shani, Aliza Katz, Ron Diskin
: To effectively infect cells, Lassa virus needs to switch in endosomal compartment from its primary receptor α-dystroglycan to a protein termed LAMP1. A unique histidine triad on the surface of the receptor-binding domain from the glycoprotein spike complex of Lassa virus is important for LAMP1 binding. Here we investigate mutated spikes that have impaired ability to interact with LAMP1 and show that although LAMP1 is important for efficient infectivity it is not required for spike-mediated membrane fusion per se...
September 7, 2016: Journal of Virology
Hirokazu Yagi, Chu-Wei Kuo, Takayuki Obayashi, Satoshi Ninagawa, Kay-Hooi Khoo, Koichi Kato
Dystroglycanopathy is a major class of congenital muscular dystrophy caused by a deficiency of functional glycans on α-dystroglycan (αDG) with laminin-binding activity. Recent advances have led to identification of several causative gene products of dystroglycanopathy and characterization of their in vitro enzymatic activities. However, the in vivo functional roles remain equivocal for enzymes such as ISPD, FKTN, FKRP, and TMEM5 that are supposed to be involved in post-phosphoryl modifications linking the GalNAc-β3-GlcNAc-β34-Man-6-phosphate core and the outer laminin-binding glycans...
September 6, 2016: Molecular & Cellular Proteomics: MCP
Freyja K McClenahan, Himanshu Sharma, Xiwei Shan, Christopher Eyermann, Holly Colognato
While the extracellular matrix (ECM) is known to regulate neural stem cell quiescence in the adult subventricular zone (SVZ), the function of ECM in the developing SVZ remains unknown. Here, we report that the ECM receptor dystroglycan regulates a unique developmental restructuring of ECM in the early postnatal SVZ. Dystroglycan is furthermore required for ependymal cell differentiation and assembly of niche pinwheel structures, at least in part by suppressing Notch activation in radial glial cells, which leads to the increased expression of MCI, Myb, and FoxJ1, transcriptional regulators necessary for acquisition of the multiciliated phenotype...
September 12, 2016: Developmental Cell
Simanti Bhattacharya, Amit Das, Angshuman Bagchi
Impaired glycosylation of cellular receptor Alpha Dystroglycan (α-DG) leads to dystroglycanopathy. Glycoprotein α-DG is the receptor protein in the Dystrophin Associated Protein Complex (DAPC), a macromolecular gathering on muscle cell membrane to form a bridge between extracellular matrix (ECM) and cellular actin cytoskeleton. Proper glycosylation of α-DG is mediated by the glycosylating enzyme LARGE. Mutations either in α-DG or in LARGE lead to improper glycosylations of α-DG thereby hampering the formation of final Laminin binding form α-DG resulting in dystroglycanopathy...
July 16, 2016: Computational Biology and Chemistry
Paul J Thomas, Rui Xu, Paul T Martin
Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of α dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin α2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo(-) mice, a model for limb girdle muscular dystrophy 2I...
September 2016: American Journal of Pathology
Adriana Izquierdo-Lahuerta, Oscar de Luis, Francisco Gómez-Esquer, Jesús Cruces, Antonio Coloma
Alpha-dystroglycanopathies are a heterogenic group of human rare diseases that have in common defects of α-dystroglycan O-glycosylation. These congenital disorders share common features as muscular dystrophy, malformations on central nervous system and more rarely altered ocular development, as well as mutations on a set of candidate genes involved on those syndromes. Severity of the syndromes is variable, appearing Walker-Warburg as the most severe where mutations at protein O-mannosyl transferases POMT1 and POMT2 genes are frequently described...
September 23, 2016: Biochemical and Biophysical Research Communications
Pingbo Zhang, Rabia Karani, Randi L Turner, Craig Dufresne, Sara Ferri, Jennifer E Van Eyk, Richard D Semba
The optic nerve is a white matter tract that conveys visual information to the brain. The sclera comprises the white, protective outer layer of the eye. A characterization of the proteome of normal human retrobulbar optic nerve and sclera may facilitate studies of the eye. We conducted a proteomic analysis of optic nerve and sclera from five adults. Proteins were fractionated using SDS-PAGE. After in-gel digestion, peptides were analyzed using LC-MS/MS on an Orbitrap Elite mass spectrometer. We identified 2711 non-redundant proteins in retrobulbar optic nerve and 1945 non-redundant proteins in sclera...
October 2016: Proteomics
Adrian J Waite, Francesca A Carlisle, Yiumo Michael Chan, Derek J Blake
BACKGROUND: Myoclonus-dystonia is a neurogenic movement disorder caused by mutations in the gene encoding ɛ-sarcoglycan. By contrast, mutations in the α-, β-, γ-, and δ-sarcoglycan genes cause limb girdle muscular dystrophies. The sarcoglycans are part of the dystrophin-associated protein complex in muscle that is disrupted in several types of muscular dystrophy. Intriguingly, patients with myoclonus-dystonia have no muscle pathology; conversely, limb-girdle muscular dystrophy patients have not been reported to have dystonia-associated features...
August 18, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
David C Briggs, Takako Yoshida-Moriguchi, Tianqing Zheng, David Venzke, Mary E Anderson, Andrea Strazzulli, Marco Moracci, Liping Yu, Erhard Hohenester, Kevin P Campbell
Dystroglycan is a highly glycosylated extracellular matrix receptor with essential functions in skeletal muscle and the nervous system. Reduced matrix binding by α-dystroglycan (α-DG) due to perturbed glycosylation is a pathological feature of several forms of muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) synthesizes the matrix-binding heteropolysaccharide [-glucuronic acid-β1,3-xylose-α1,3-]n. Using a dual exoglycosidase digestion, we confirm that this polysaccharide is present on native α-DG from skeletal muscle...
October 2016: Nature Chemical Biology
Elizabeth Keramaris, Pei J Lu, Jason Tucker, Qi L Lu
INTRODUCTION: Mutations in the Fukutin related protein (FKRP) gene are characterized by a lack of functionally glycosylated α-dystroglycan (F-α-DG) in muscles. A small number of fibers retain the capacity to produce strong IIH6 reactive glycosylated-α-DG (g-α-DG) in muscles of both FKRP mutant animals and patients. METHODS: We examined the expression of g-α-DG in limb, diaphragm, and cardiac muscles of newborn FKRP mutants and LARGE(myd) mice with IIH6 antibody...
August 12, 2016: Muscle & Nerve
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