DOCSLIB.ORG

What Do We Know About Dystroglycan?

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
What Do We Know About Dystroglycan? What Do We Know about Dystroglycan? Daniel Beltran 1 Outline 1. Basement membrane in epithelium and skeletal muscle. 2. Role of dystroglycan. 3. Muscle contraction and repair under normal conditions. 4. Dystroglycanopathies genetics. 5. Dystroglycanopathies muscle pathology. 2 Outline 1. Basement membrane in epithelium and skeletal muscle. 2. Role of dystroglycan. 3. Muscle contraction and repair under normal conditions. 4. Dystroglycanopathies genetics. 5. Dystroglycanopathies muscle pathology. 3 The human body: Cells and connections 4 The human body: Cells and connections Communication and …………… Contact 5 Basement Membrane Basement membrane 6 Basement Membrane Functions Adhesion Mechanic stability Polarity Survival Compartmentalization Proliferation More than just structure 7 Skeletal Muscle 8 Skeletal Muscle Basal Lamina Kjaer (2004). Physiological Reviews, 84: 649. 9 Skeletal Muscle Basal lamina Mouse skeletal muscle Human skeletal muscle 10 Goddeeris et al (2013). Nature, 503:136 Sabatelli et al (2003). Biochim Biophys Acta, 1638:57 Outline 1. Basement membrane in epithelium and skeletal muscle. 2. Role of dystroglycan. 3. Muscle contraction and repair under normal conditions. 4. Dystroglycanopathies genetics. 5. Dystroglycanopathies muscle pathology. 11 Dystroglycan Basement Membrane Laminin α Dystroglycan Membrane β Dystrophin 12 Basement Membrane compaction Colognato 1999. JCB, 145:619 13 Outline 1. Basement membrane in epithelium and skeletal muscle. 2. Role of dystroglycan. 3. Muscle contraction and repair under normal conditions. • Contraction. • Contraction induced muscle damage. • Sarcolemma repair. • Satellite cells mediated muscle repair. • Debris clearance and extracellular remodeling. 14 Muscle Contraction 15 Transmission of force DGC might contribute to “lateral transmission of force” from the sarcomere to the lateral extracellular matrix. 16 Muscle Fiber Repair Han et al (2007). Curr. Opin. Cell Biol., 19:409. 17 Satellite Cells Satellite cells are quiescent unipotent stem cells, located underneath the basal lamina of adult skeletal muscle fibers Basement membrane 18 From Yin et al (2013). Physiological Reviews, 93:23. T cells T Mast Neut Well Well integrated for a healthy muscle INFLAMMATION Immune cells and fibroblasts and cells Immune 19 Lieber et al (2014). Am J Physiol Cell Physiol, 305:C241 Outline 1. Basement membrane in epithelium and skeletal muscle. 2. Role of dystroglycan. 3. Muscle contraction and repair under normal conditions. 4. Dystroglycanopathy genes. 5. Dystroglycanopathies muscle pathology. 20 Loss of α-Dystroglycan functional glycosylation Normal Dystroglycanopathy Dystroglycanopathies spectrum Congenital muscular dystrophy CMD CMD w/ brain involvement Walker-Warburg LGMD no brain involvement Muscle-Eye-Brain (MEB) (WWS) Fukuyama-CMD (FCMD) Severity Adapted from Tobias Willer Dystroglycan Glycosylation Process Generated byTobias Willer 23 Dystroglycanopathy candidate genes Generated byTobias Willer Introduction of exome sequencing Loss of α-Dystroglycan functional glycosylation Normal Dystroglycanopathy Outline 1. Basement membrane in epithelium and skeletal muscle. 2. Role of dystroglycan. 3. Muscle contraction and repair under normal conditions. 4. Dystroglycanopathy genes. 5. Dystroglycanopathies muscle pathology. • Contraction. • Contraction induced muscle damage. • Sarcolemma repair. • Satellite cells mediated muscle repair. • Debris clearance and extracellular remodeling. 26 Muscle Force Deficit Lateral transmission of force Dystrophic muscle displays considerable muscle weakness even in very early stages of the disease, prior to muscular atrophy. Muscle as a unit 27 Model: αDG Large-glycan as a tunable scaffold for the basement membrane. Generated by Matt Goddeeris Dystroglycan 28 Generated by Matt Goddeeris Basement Membrane compaction Typical amount of glycan Reduced glycan Large-KD Collagen Superstructure Collagen Superstructure BM { Laminin Superstructure Laminin Superstructure Sarcolemma Sarcolemma 29 Laser membrane damage assay Wild type Wild Hypoglycosylated dystroglycan Wild type dystroglycan Hypoglycosylated Fracture mechanics of the plasma membrane Normal DGC * Satellite cells Dystroglycan plays a role in the attachment and/or stability of satellite cells. Basal lamina components in the are known to govern satellite cell behavior; laminin-211 is particularly important. Satellite cells in the muscles become exhausted, losing their regenerative capacity Normal Ross et al (2012). Stem Cells, 30:2330. Proliferation is More fibronectin and α compromised in myd CSs collagen in myd β DGpathy α β From Yin et al (2013). Physiological Reviews, 93:23. 32 The human body: Cells and connections Communication and …………… Contact 33 T cells T Mast Neut INFLAMMATION Immune cells and fibroblasts and cells Immune 34 Lieber et al (2014). Am J Physiol Cell Physiol, 305:C241 Possible Therapies • Contraction. • Contraction induced muscle damage. • Muscle Fiber repair. • Satellite cells fate. • Satellite cells exhaustion. • Immune response and fibrosis. 35 Possible Therapies Binding site Agrin GalN β1,3 GlcN P ? n β1,4 Xyl GlcA Man LARGE Perlecan Pomt1/2 Laminin O α S/T α Pharmacotherapy: β Upregulate glycosylation. Upregulate LARGE. Gene Therapy: AAV gene delivery (FKRP, LARGE) 36 Possible Therapies Pharmacotherapy: Vasodilator Anti inflammatories SCs directed therapies Cell Therapy: Modification of patient SCs Cell Transplantation Madaro & Bouche (2014). Biomed Res Int, 2014: 438675 37 THANK YOU! 38 .
Load more

Recommended publications
  • Profiling of the Muscle-Specific Dystroglycan Interactome Reveals the Role of Hippo Signaling in Muscular Dystrophy and Age-Dependent Muscle Atrophy Andriy S
    Yatsenko et al. BMC Medicine (2020) 18:8 https://doi.org/10.1186/s12916-019-1478-3 RESEARCH ARTICLE Open Access Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy Andriy S. Yatsenko1†, Mariya M. Kucherenko2,3,4†, Yuanbin Xie2,5†, Dina Aweida6, Henning Urlaub7,8, Renate J. Scheibe1, Shenhav Cohen6 and Halyna R. Shcherbata1,2* Abstract Background: Dystroglycanopathies are a group of inherited disorders characterized by vast clinical and genetic heterogeneity and caused by abnormal functioning of the ECM receptor dystroglycan (Dg). Remarkably, among many cases of diagnosed dystroglycanopathies, only a small fraction can be linked directly to mutations in Dg or its regulatory enzymes, implying the involvement of other, not-yet-characterized, Dg-regulating factors. To advance disease diagnostics and develop new treatment strategies, new approaches to find dystroglycanopathy-related factors should be considered. The Dg complex is highly evolutionarily conserved; therefore, model genetic organisms provide excellent systems to address this challenge. In particular, Drosophila is amenable to experiments not feasible in any other system, allowing original insights about the functional interactors of the Dg complex. Methods: To identify new players contributing to dystroglycanopathies, we used Drosophila as a genetic muscular dystrophy model. Using mass spectrometry, we searched for muscle-specific Dg interactors. Next, in silico analyses allowed us to determine their association with diseases and pathological conditions in humans. Using immunohistochemical, biochemical, and genetic interaction approaches followed by the detailed analysis of the muscle tissue architecture, we verified Dg interaction with some of the discovered factors.
    [Show full text]
  • Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells
    10296 • The Journal of Neuroscience, October 5, 2016 • 36(40):10296–10313 Cellular/Molecular Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells Simon Fru¨h,1,5 Jennifer Romanos,1,5 Patrizia Panzanelli,2 XDaniela Bu¨rgisser,3 XShiva K. Tyagarajan,1,5 X Kevin P. Campbell,4 XMirko Santello,1,5 and XJean-Marc Fritschy1,5 1Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, 2Department of Neuroscience Rita Levi Montalcini, University of Turin, 10124 Turin, Italy, 3ETH Zurich, 8092 Zurich, Switzerland, 4Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, and 5Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland 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 unex- plored. 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. Conditional deletion of Dag1, encoding dystrogly- can, in pyramidal cells caused loss of CCK-positive basket cell terminals in hippocampus and neocortex. PV-positive basket cell terminals were unaffected in mutant mice, demonstrating interneuron subtype-specific function of dystroglycan. Loss of dystroglycan in pyrami- dal cells had little influence on clustering of other GABAergic postsynaptic proteins and of glutamatergic synaptic proteins.
    [Show full text]
  • Advanced Fiber Type-Specific Protein Profiles Derived from Adult Murine
    proteomes Article Advanced Fiber Type-Specific Protein Profiles Derived from Adult Murine Skeletal Muscle Britta Eggers 1,2,* , Karin Schork 1,2, Michael Turewicz 1,2 , Katalin Barkovits 1,2 , Martin Eisenacher 1,2, Rolf Schröder 3, Christoph S. Clemen 4,5 and Katrin Marcus 1,2,* 1 Medizinisches Proteom-Center, Medical Faculty, Ruhr-University Bochum, 44801 Bochum, Germany; [email protected] (K.S.); [email protected] (M.T.); [email protected] (K.B.); [email protected] (M.E.) 2 Medical Proteome Analysis, Center for Protein Diagnostics (PRODI), Ruhr-University Bochum, 44801 Bochum, Germany 3 Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany; [email protected] 4 German Aerospace Center, Institute of Aerospace Medicine, 51147 Cologne, Germany; [email protected] 5 Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, 50931 Cologne, Germany * Correspondence: [email protected] (B.E.); [email protected] (K.M.) Abstract: Skeletal muscle is a heterogeneous tissue consisting of blood vessels, connective tissue, and muscle fibers. The last are highly adaptive and can change their molecular composition depending on external and internal factors, such as exercise, age, and disease. Thus, examination of the skeletal muscles at the fiber type level is essential to detect potential alterations. Therefore, we established a protocol in which myosin heavy chain isoform immunolabeled muscle fibers were laser Citation: Eggers, B.; Schork, K.; microdissected and separately investigated by mass spectrometry to develop advanced proteomic Turewicz, M.; Barkovits, K.; profiles of all murine skeletal muscle fiber types.
    [Show full text]
  • B3GALNT2 Is a Gene Associated with Congenital Muscular Dystrophy with Brain Malformations
    European Journal of Human Genetics (2014) 22, 707–710 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg SHORT REPORT B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations Carola Hedberg*,1, Anders Oldfors1 and Niklas Darin2 Congenital muscular dystrophies associated with brain malformations are a group of disorders frequently associated with aberrant glycosylation of a-dystroglycan. They include disease entities such a Walker–Warburg syndrome, muscle–eye–brain disease and various other clinical phenotypes. Different genes involved in glycosylation of a-dystroglycan are associated with these dystroglycanopathies. We describe a 5-year-old girl with psychomotor retardation, ataxia, spasticity, muscle weakness and increased serum creatine kinase levels. Immunhistochemistry of skeletal muscle revealed reduced glycosylated a-dystroglycan. Magnetic resonance imaging of the brain at 3.5 years of age showed increased T2 signal from supratentorial and infratentorial white matter, a hypoplastic pons and subcortical cerebellar cysts. By whole exome sequencing, the patient was identified to be compound heterozygous for a one-base duplication and a missense mutation in the gene B3GALNT2 (b-1,3-N-acetylgalactos- aminyltransferase 2; B3GalNAc-T2). This patient showed a milder phenotype than previously described patients with mutations in the B3GALNT2 gene. European Journal of Human Genetics (2014) 22, 707–710; doi:10.1038/ejhg.2013.223; published online 2 October 2013 Keywords:
    [Show full text]
  • An Adhesome Comprising Laminin, Dystroglycan and Myosin IIA Is
    © 2014. Published by The Company of Biologists Ltd | Development (2014) 141, 4569-4579 doi:10.1242/dev.116103 RESEARCH ARTICLE An adhesome comprising laminin, dystroglycan and myosin IIA is required during notochord development in Xenopus laevis Nicolas Buisson1, Cathy Sirour2, Nicole Moreau1, Elsa Denker3, Ronan Le Bouffant1, Aline Goullancourt1, Thierry Darriberè 1,* and Valérie Bello1,* ABSTRACT final step, vacuolation, which begins in cells at the anterior and Dystroglycan (Dg) is a transmembrane receptor for laminin that must progesses through to the posterior end of embryos, provides both be expressed at the right time and place in order to be involved stiffness and an increase in cell volume, leading to notochord in notochord morphogenesis. The function of Dg was examined in elongation. Vacuoles are lysosome-related organelles that form Xenopus laevis embryos by knockdown of Dg and overexpression and through a Rab protein and vacuolar-type proton-ATPase-dependent replacement of the endogenous Dg with a mutated form of the protein. acidification (Ellis et al., 2013). The peri-notochordal sheath, in This analysis revealed that Dg is required for correct laminin assembly, combination with the turgor pressure exerted by vacuolated cells, for cell polarization during mediolateral intercalation and for proper provides the rigidity of the notochord that is required for its function differentiation of vacuoles. Using mutations in the cytoplasmic as the major skeletal element of embryos. Although the functions of domain, we identified two sites that are involved in cell polarization integrin in these mechanisms have already been studied (Davidson and are required for mediolateral cell intercalation, and a site that is et al., 2006), there is no information on the involvement of required for vacuolation.
    [Show full text]
  • Muscle Diseases: the Muscular Dystrophies
    ANRV295-PM02-04 ARI 13 December 2006 2:57 Muscle Diseases: The Muscular Dystrophies Elizabeth M. McNally and Peter Pytel Department of Medicine, Section of Cardiology, University of Chicago, Chicago, Illinois 60637; email: [email protected] Department of Pathology, University of Chicago, Chicago, Illinois 60637; email: [email protected] Annu. Rev. Pathol. Mech. Dis. 2007. Key Words 2:87–109 myotonia, sarcopenia, muscle regeneration, dystrophin, lamin A/C, The Annual Review of Pathology: Mechanisms of Disease is online at nucleotide repeat expansion pathmechdis.annualreviews.org Abstract by Drexel University on 01/13/13. For personal use only. This article’s doi: 10.1146/annurev.pathol.2.010506.091936 Dystrophic muscle disease can occur at any age. Early- or childhood- onset muscular dystrophies may be associated with profound loss Copyright c 2007 by Annual Reviews. All rights reserved of muscle function, affecting ambulation, posture, and cardiac and respiratory function. Late-onset muscular dystrophies or myopathies 1553-4006/07/0228-0087$20.00 Annu. Rev. Pathol. Mech. Dis. 2007.2:87-109. Downloaded from www.annualreviews.org may be mild and associated with slight weakness and an inability to increase muscle mass. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and Z band, as well as nuclear membrane components. Because muscle has such distinctive structural and regenerative properties, many of the genes implicated in these disorders target pathways unique to muscle or more highly expressed in muscle.
    [Show full text]
  • Desmin Is a Modifier of Dystrophic Muscle Features in Mdx Mice
    bioRxiv preprint doi: https://doi.org/10.1101/742858; this version posted August 23, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Desmin is a modifier of dystrophic muscle features in Mdx mice Arnaud Ferry (1,2), Julien Messéant (1), Ara Parlakian (3), Mégane Lemaitre (1), Pauline Roy (1), Clément Delacroix (1), Alain Lilienbaum (4), Yeranuhi Hovhannisyan (3), Denis Furling (1), Arnaud Klein (1), Zhenlin Li (3), Onnik Agbulut (3) 1-Sorbonne Université, INSERM U974, CNRS UMR7215, Institut de Myologie, Paris, F- 75013 France 2-Université de Paris, Institut des Sciences du Sport Santé de Paris, Paris, F-75006 France 3- Sorbonne Université, Institut de Biologie Paris-Seine (IBPS), UMR CNRS 8256, INSERM ERL U1164, Biological Adaptation and Ageing, Paris, F-75005 France. 4-Université de Paris, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, F-75013 France. Corresponding author: Arnaud Ferry 1 bioRxiv preprint doi: https://doi.org/10.1101/742858; this version posted August 23, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract (175 words) Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease, caused by dystrophin deficiency. Desmin is like dystrophin associated to costameric structures bridging sarcomeres to extracellular matrix that are involved in force transmission and skeletal muscle integrity. In the present study, we wanted to gain further insight into the roles of desmin which expression is increased in the muscle from the mouse Mdx DMD model.
    [Show full text]
  • Dystrobrevin and Desmin
    Desmuslin, an intermediate filament protein that interacts with ␣-dystrobrevin and desmin Yuji Mizuno*, Terri G. Thompson*, Jeffrey R. Guyon*, Hart G. W. Lidov*, Melissa Brosius*, Michihiro Imamura†, Eijiro Ozawa†, Simon C. Watkins‡, and Louis M. Kunkel*§ *Howard Hughes Medical Institute͞Division of Genetics, Children’s Hospital and Harvard Medical School, Boston, MA 02115; †National Institute of Neuroscience, National Center for Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; and ‡Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15261 Contributed by Louis M. Kunkel, March 28, 2001 Dystrobrevin is a component of the dystrophin-associated protein (19), the rabbit 94-kDa protein (A0) (20), and ␤-dystrobrevin complex and has been shown to interact directly with dystrophin, (21). ␣-Dystrobrevin 1 has a unique C-terminal region with ␣1-syntrophin, and the sarcoglycan complex. The precise role of multiple sites for tyrosine phosphorylation and is highly ex- ␣-dystrobrevin in skeletal muscle has not yet been determined. To pressed in muscle and brain. This protein has two predicted study ␣-dystrobrevin’s function in skeletal muscle, we used the ␣-helical coiled-coil motifs and has been shown to interact yeast two-hybrid approach to look for interacting proteins. Three directly with ␣1-syntrophin (16, 17) and dystrophin (12). The overlapping clones were identified that encoded an intermediate ␣-dystrobrevin 2 splice form is slightly different in that it lacks filament protein we subsequently named desmuslin (DMN). Se- the unique C-terminal region and thus would not be phosphor- quence analysis revealed that DMN has a short N-terminal domain, ylated. ␣-Dystrobrevin 3 has an alternatively spliced 3Ј end that a conserved rod domain, and a long C-terminal domain, all common is more truncated than that of ␣-dystrobrevin 2.
    [Show full text]
  • Dystroglycan & Insulin Receptor Tyrosine
    University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 1999-04-02 Structural and Signaling Proteins at the Synapse: Dystroglycan & Insulin Receptor Tyrosine Kinase Substrate p58/53: a Dissertation Mary-Alice Abbott University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Amino Acids, Peptides, and Proteins Commons, Cells Commons, Enzymes and Coenzymes Commons, Hormones, Hormone Substitutes, and Hormone Antagonists Commons, and the Nervous System Commons Repository Citation Abbott M. (1999). Structural and Signaling Proteins at the Synapse: Dystroglycan & Insulin Receptor Tyrosine Kinase Substrate p58/53: a Dissertation. GSBS Dissertations and Theses. https://doi.org/ 10.13028/3sm1-jn54. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/124 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. A Dissertation Presented MAY -ALICE ABBOT Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences Worcester Massachusetts in partial fulfillment of the degree of: DOCTOR OF PHILOSOPHY APRIL 2 I 1999 BIOMEDICA SCIENCES Neil Aronin, Chair of the Committee Roger Davis, Member of the Committee Steve Doxsey, Member of the Committee Craig Ferris, Member of the Committee Lou Kunkel, Member of the Committee Justin Fallon, Dissertation Mentor Thomas Miller, Dean of the Graduate School of Biomedical Sciences ACKNOWLEDGMENTS Many thanks to Justin Fallon, a fine teacher and role model, and to my excellent co-workers/friends: David Wells, Kate Deyst, Beth McKechnie, Laura Megeath, and Mike Rafii.
    [Show full text]
  • Muscular Dystrophies Involving the Dystrophin–Glycoprotein Complex: an Overview of Current Mouse Models Madeleine Durbeej and Kevin P Campbell*
    349 Muscular dystrophies involving the dystrophin–glycoprotein complex: an overview of current mouse models Madeleine Durbeej and Kevin P Campbell* The dystrophin–glycoprotein complex (DGC) is a multisubunit dystrophies are a heterogeneous group of disorders. complex that connects the cytoskeleton of a muscle fiber to its Patients with DMD have a childhood onset phenotype and surrounding extracellular matrix. Mutations in the DGC disrupt die by their early twenties as a result of either respiratory the complex and lead to muscular dystrophy. There are a few or cardiac failure, whereas patients with BMD have naturally occurring animal models of DGC-associated moderate weakness in adulthood and may have normal life muscular dystrophy (e.g. the dystrophin-deficient mdx mouse, spans. The limb–girdle muscular dystrophies have a dystrophic golden retriever dog, HFMD cat and the highly variable onset and progression, but the unifying δ-sarcoglycan-deficient BIO 14.6 cardiomyopathic hamster) theme among the limb–girdle muscular dystrophies is the that share common genetic protein abnormalities similar to initial involvement of the shoulder and pelvic girdle those of the human disease. However, the naturally occurring muscles. Moreover, muscular dystrophies may or may not animal models only partially resemble human disease. In be associated with cardiomyopathy [1–4]. addition, no naturally occurring mouse models associated with loss of other DGC components are available. This has Combined positional cloning and candidate gene encouraged the generation of genetically engineered mouse approaches have been used to identify an increasing number models for DGC-linked muscular dystrophy. Not only have of genes that are mutated in various forms of muscular analyses of these mice led to a significant improvement in our dystrophy.
    [Show full text]
  • The Regulation of Beta- Dystroglycan Internalization
    The Regulation of Beta- Dystroglycan Internalization Robert Piggott A thesis submitted to the University of Sheffield for the degree of Doctor of Philosophy Department of Biomedical Sciences, University of Sheffield July 2014 I TABLE OF CONTENTS CONTENTS………………………………………………………………………………II ABBREVIATIONS LIST…………………………………………………………....……VI ABSTRACT……………………………………………………………………………..VIII Chapter 1: Introduction .................................................................................. 1 1.1.1 The Dystroglycan Subunits ..................................................................... 2 1.1.2 Dystroglycan is an Essential Adhesion Protein......................................... 4 1.1.3 Dystroglycan in the Dystrophin-associated Glycoprotein Complex ............ 5 1.1.4 Dystroglycan in Other Complexes ......................................................... 10 1.1.5 Dystroglycan Complex Formation in Response to the Extracellular Matrix ................................................................................................................... 13 1.1.6 Summary: Why Dystroglycan is an Essential Protein.............................. 15 1.2.1 Duchenne Muscular Dystrophy ............................................................. 17 1.2.2 The mdx Mouse and Other Models ........................................................ 19 1.2.3 Dystroglycan Disruption and Other Muscular Dystrophies ...................... 22 1.2.4 Summary: The Loss and Restoration of β-Dystroglycan in DMD Pathology and Therapy ................................................................................................
    [Show full text]
  • Synemin-Related Skeletal and Cardiac Myopathies
    Synemin-related skeletal and cardiac myopathies: an overview of pathogenic variants Denise Paulin, Yeranuhi Hovannisyan, Serdar Kasakyan, Onnik Agbulut, Zhenlin Li, Zhigang Xue To cite this version: Denise Paulin, Yeranuhi Hovannisyan, Serdar Kasakyan, Onnik Agbulut, Zhenlin Li, et al.. Synemin- related skeletal and cardiac myopathies: an overview of pathogenic variants. American Journal of Physiology - Cell Physiology, American Physiological Society, 2020, 318 (4), pp.C709-C718. 10.1152/ajpcell.00485.2019. hal-03000985 HAL Id: hal-03000985 https://hal.archives-ouvertes.fr/hal-03000985 Submitted on 12 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Copyright 1 Synemin-related skeletal and cardiac myopathies: an overview of pathogenic variants 2 3 Denise Paulin1, Yeranuhi Hovannisyan1, Serdar Kasakyan2, Onnik Agbulut1, Zhenlin Li1*, 4 Zhigang Xue1 5 6 1 Sorbonne Université, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8256, INSERM 7 ERL U1164, Biological Adaptation and Ageing, 75005, Paris, France. 8 2 Duzen Laboratories Group, Center of Genetic Diagnosis, 34394, Istanbul, Turkey. 9 10 11 Running title: Synemin polymorphism and related myopathies 12 13 14 15 *Corresponding Author: 16 Dr Zhenlin Li, Sorbonne Université, Institut de Biologie Paris-Seine, UMR CNRS 8256, 17 INSERM ERL U1164, 7, quai St Bernard - case 256 - 75005 Paris-France.
    [Show full text]