Structural Abnormalities at Neuromuscular Synapses Lacking Multiple Syntrophin Isoforms
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Genetic Mutations and Mechanisms in Dilated Cardiomyopathy
Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, … , Jessica R. Golbus, Megan J. Puckelwartz J Clin Invest. 2013;123(1):19-26. https://doi.org/10.1172/JCI62862. Review Series Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia. Find the latest version: https://jci.me/62862/pdf Review series Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, Jessica R. Golbus, and Megan J. Puckelwartz Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of conges- tive heart failure. -
Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy
International Journal of Molecular Sciences Review Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy Aoife Gowran 1,*, Maura Brioschi 2, Davide Rovina 1 , Mattia Chiesa 3,4 , Luca Piacentini 3,* , Sara Mallia 1, Cristina Banfi 2,* , Giulio Pompilio 1,5,6,* and Rosaria Santoro 1,4 1 Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy; [email protected] (D.R.); [email protected] (S.M.); [email protected] (R.S.) 2 Unit of Cardiovascular Proteomics, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy; [email protected] 3 Bioinformatics and Artificial Intelligence Facility, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy; [email protected] 4 Department of Electronics, Information and Biomedical Engineering, Politecnico di Milano, 20133 Milan, Italy 5 Department of Cardiac Surgery, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy 6 Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy * Correspondence: [email protected] (A.G.); [email protected] (L.P.); cristina.banfi@cardiologicomonzino.it (C.B.); [email protected] (G.P.) Abstract: Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling Citation: Gowran, A.; Brioschi, M.; abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy Rovina, D.; Chiesa, M.; Piacentini, L.; (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also Mallia, S.; Banfi, C.; Pompilio, G.; Santoro, R. -
'Clustering of Nicotinic Acetylcholine Receptors: from the Neuromuscular
Huh, K H; Fuhrer, C. Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses. Mol. Neurobiol. 2002, 25(1):79-112. Postprint available at: http://www.zora.unizh.ch University of Zurich Posted at the Zurich Open Repository and Archive, University of Zurich. Zurich Open Repository and Archive http://www.zora.unizh.ch Originally published at: Mol. Neurobiol. 2002, 25(1):79-112 Winterthurerstr. 190 CH-8057 Zurich http://www.zora.unizh.ch Year: 2002 Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses Huh, K H; Fuhrer, C Huh, K H; Fuhrer, C. Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses. Mol. Neurobiol. 2002, 25(1):79-112. Postprint available at: http://www.zora.unizh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.unizh.ch Originally published at: Mol. Neurobiol. 2002, 25(1):79-112 Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses Abstract Fast and accurate synaptic transmission requires high-density accumulation of neurotransmitter receptors in the postsynaptic membrane. During development of the neuromuscular junction, clustering of acetylcholine receptors (AChR) is one of the first signs of postsynaptic specialization and is induced by nerve-released agrin. Recent studies have revealed that different mechanisms regulate assembly vs stabilization of AChR clusters and of the postsynaptic apparatus. MuSK, a receptor tyrosine kinase and component of the agrin receptor, and rapsyn, an AChR-associated anchoring protein, play crucial roles in the postsynaptic assembly. Once formed, AChR clusters and the postsynaptic membrane are stabilized by components of the dystrophin/utrophin glycoprotein complex, some of which also direct aspects of synaptic maturation such as formation of postjunctional folds. -
Dystrophin Complex Functions As a Scaffold for Signalling Proteins☆
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1838 (2014) 635–642 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamem Review Dystrophin complex functions as a scaffold for signalling proteins☆ Bruno Constantin IPBC, CNRS/Université de Poitiers, FRE 3511, 1 rue Georges Bonnet, PBS, 86022 Poitiers, France article info abstract Article history: Dystrophin is a 427 kDa sub-membrane cytoskeletal protein, associated with the inner surface membrane and Received 27 May 2013 incorporated in a large macromolecular complex of proteins, the dystrophin-associated protein complex Received in revised form 22 August 2013 (DAPC). In addition to dystrophin the DAPC is composed of dystroglycans, sarcoglycans, sarcospan, dystrobrevins Accepted 28 August 2013 and syntrophin. This complex is thought to play a structural role in ensuring membrane stability and force trans- Available online 7 September 2013 duction during muscle contraction. The multiple binding sites and domains present in the DAPC confer the scaf- fold of various signalling and channel proteins, which may implicate the DAPC in regulation of signalling Keywords: Dystrophin-associated protein complex (DAPC) processes. The DAPC is thought for instance to anchor a variety of signalling molecules near their sites of action. syntrophin The dystroglycan complex may participate in the transduction of extracellular-mediated signals to the muscle Sodium channel cytoskeleton, and β-dystroglycan was shown to be involved in MAPK and Rac1 small GTPase signalling. More TRPC channel generally, dystroglycan is view as a cell surface receptor for extracellular matrix proteins. -
Dystrobrevin: Roles in Skeletal Muscle and Its Neuromuscular and Myotendinous Junctions R
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Digital Commons@Becker Washington University School of Medicine Digital Commons@Becker Open Access Publications 2-25-2003 Tyrosine-phosphorylated and nonphosphorylated isoforms of α-dystrobrevin: roles in skeletal muscle and its neuromuscular and myotendinous junctions R. Mark Grady Washington University School of Medicine in St. Louis Mohammed Akaaboune Washington University School of Medicine in St. Louis Alexander L. Cohen Washington University School of Medicine in St. Louis Margaret M. Maimone State University of New York Upstate Medical University Jeff .W Lichtman Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: http://digitalcommons.wustl.edu/open_access_pubs Part of the Medicine and Health Sciences Commons Recommended Citation Grady, R. Mark; Akaaboune, Mohammed; Cohen, Alexander L.; Maimone, Margaret M.; Lichtman, Jeff .;W and Sanes, Joshua R., ,"Tyrosine-phosphorylated and nonphosphorylated isoforms of α-dystrobrevin: roles in skeletal muscle and its neuromuscular and myotendinous junctions." The ourJ nal of Cell Biology.160,5. 741-752. (2003). http://digitalcommons.wustl.edu/open_access_pubs/625 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors R. Mark Grady, Mohammed Akaaboune, Alexander L. Cohen, Margaret M. Maimone, Jeff .W Lichtman, and Joshua R. Sanes This open access publication is available at Digital Commons@Becker: http://digitalcommons.wustl.edu/open_access_pubs/625 Published February 25, 2003 JCBArticle Tyrosine-phosphorylated and nonphosphorylated isoforms of ␣-dystrobrevin: roles in skeletal muscle and its neuromuscular and myotendinous junctions R. -
Muscle Disorders
Brain Pathology 7: 1289-1291 (1997) KEYNOTE LECTURE KL5.1 - Muscle Disorders KL5.1 Molecular diagnosis of muscular dystrophies various tissues and identified as the 156kDaa-dystro- glycan and 43kDap-dystroglycan in skeletal muscle. Dr. Hideo Sugita a-dystroglycan , an extracellular protein, binds to one National Center of Neurology and Psychiatry, Kodaira Tokyo of the main components of the extracellular matrix, 187, Japan laminin probably through its sugar chains. a-dystroglycan binds to P-dystroglycan, a trans- The muscular dystrophies comprise clinically and membraneous pro1 ein. genetically heterogeneous group of disorders. Inside the mussle cell, a-dystroglycan binds to the Since the discovery of the gene and gene product of cysteine-rich domain and fxst half of the C-terminal Duchenne (DMD)/Becker muscular dystrophy (BMD), domain of dystrorhin. At the N--terminal regions, dys- dystrophin by Louis Kunkel's group in late 1980, enor- trophin molecule binds to actin-filament. mous progress has been achieved in understanding the There is a connecting axis anchored by laminin pathomechanism, as well as the diagnosis of between the subsarcolemmal cytoskeletons and extra- DMDBMD and related muscular dystrophies at the cellular matrix, which is called the "dystrophin-axis" ( molecular level. actin-dystrophin-dystroglycan complex). In addition to interest in dystrophin, defects of which This axis may play an important role to construct a give rise to DMDBMD, much interest of researchers in cell-matrix adhesion junction to fix the sarcolemma to muscular dystrophies has been concentrated to plasma the mechanically tough basal lamina, forming a protec- membrane and its associated architectures of muscle tion system to the sarcolemma during contraction and fibers. -
Analysis of the Dystrophin Interactome
Analysis of the dystrophin interactome Dissertation In fulfillment of the requirements for the degree “Doctor rerum naturalium (Dr. rer. nat.)” integrated in the International Graduate School for Myology MyoGrad in the Department for Biology, Chemistry and Pharmacy at the Freie Universität Berlin in Cotutelle Agreement with the Ecole Doctorale 515 “Complexité du Vivant” at the Université Pierre et Marie Curie Paris Submitted by Matthew Thorley born in Scunthorpe, United Kingdom Berlin, 2016 Supervisor: Simone Spuler Second examiner: Sigmar Stricker Date of defense: 7th December 2016 Dedicated to My mother, Joy Thorley My father, David Thorley My sister, Alexandra Thorley My fiancée, Vera Sakhno-Cortesi Acknowledgements First and foremost, I would like to thank my supervisors William Duddy and Stephanie Duguez who gave me this research opportunity. Through their combined knowledge of computational and practical expertise within the field and constant availability for any and all assistance I required, have made the research possible. Their overarching support, approachability and upbeat nature throughout, while granting me freedom have made this year project very enjoyable. The additional guidance and supported offered by Matthias Selbach and his team whenever required along with a constant welcoming invitation within their lab has been greatly appreciated. I thank MyoGrad for the collaboration established between UPMC and Freie University, creating the collaboration within this research project possible, and offering research experience in both the Institute of Myology in Paris and the Max Delbruck Centre in Berlin. Vital to this process have been Gisele Bonne, Heike Pascal, Lidia Dolle and Susanne Wissler who have aided in the often complex processes that I am still not sure I fully understand. -
Review Increasing Complexity of the Dystrophin-Associated Protein Complex Jonathon M
Proc. Nadl. Acad. Sci. USA Vol. 91, pp. 8307-8313, August 1994 Review Increasing complexity of the dystrophin-associated protein complex Jonathon M. Tinsley, Derek J. Blake, Richard A. Zuellig, and Kay E. Davies Molecular Genetics Group, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom ABSTRACT Duchenne muscular dys- Purkinje neurons. Alternatively spliced dystrophin-1 (Dp7l) and apo-dystro- trophy is a severe X chromosome-linked, isoforms originating from the carboxyl- phin-3 are regulated by a promoter situ- muscle-wasting disease caused by lack of terminal coding region ofdystrophin have ated between exons 62 and 63 of the the protein dystrophin. The exact function also been described. The significance of dystrophin gene and are expressed in of dystrophin rem to be determined. these isoforms at the RNA and protein nonmuscle tissues, including brain, lung, However, analysis of its interaction with a level has not been elucidated. liver, and kidney. Apo-dystrophin-1 tran- large oligomeric protein complex at the Dystrophin is a 427-kDa protein local- scripts are only detectable in fetal and sarcolemma and the identicaton of a ized to the cytoplasmic face of the sar- newborn muscle. Muscle samples taken structurally related protein, utrophin, is colemma, enriched at myotendinous after 15 days postnatally have no apo- leading to the characterization ofcandidate junctions and the postsynaptic mem- dystrophin-1 transcript as determined by genes for other neuromusular disorders. brane of the neuromuscular junction reverse transcription-PCR. In rat brain, (NMJ). Dystrophin colocalizes with apo-dystrophin-1 transcripts continue in- Duchenne muscular dystrophy (DMD) is f3-spectrin and vinculin in three distinct creasing until they reach a maximum the most common muscular dystrophy, domains at the sarcolemma (overlaying after -1 mo. -
Α-Dystrobrevin-1 Recruits Α-Catulin to the Α1d- Adrenergic Receptor/Dystrophin-Associated Protein Complex Signalosome
α-Dystrobrevin-1 recruits α-catulin to the α1D- adrenergic receptor/dystrophin-associated protein complex signalosome John S. Lyssanda, Jennifer L. Whitingb, Kyung-Soon Leea, Ryan Kastla, Jennifer L. Wackera, Michael R. Bruchasa, Mayumi Miyatakea, Lorene K. Langebergb, Charles Chavkina, John D. Scottb, Richard G. Gardnera, Marvin E. Adamsc, and Chris Haguea,1 Departments of aPharmacology and cPhysiology and Biophysics, University of Washington, Seattle, WA 98195; and bDepartment of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Edited by Robert J. Lefkowitz, Duke University Medical Center/Howard Hughes Medical Institute, Durham, NC, and approved October 29, 2010 (received for review July 22, 2010) α1D-Adrenergic receptors (ARs) are key regulators of cardiovascu- pression increases in patients with benign prostatic hypertrophy lar system function that increase blood pressure and promote vas- (12). Through proteomic screening, we discovered that α1D-ARs cular remodeling. Unfortunately, little information exists about are scaffolded to the dystrophin-associated protein complex the signaling pathways used by this important G protein-coupled (DAPC) via the anchoring protein syntrophin (10). Coexpression α “ α receptor (GPCR). We recently discovered that 1D-ARs form a sig- with syntrophins increases 1D-AR plasma membrane expression, nalosome” with multiple members of the dystrophin-associated drug binding, and activation of Gαq/11 signaling after agonist protein complex (DAPC) to become functionally expressed at the activation. Moreover, syntrophin knockout mice lose α1D-AR– plasma membrane and bind ligands. However, the molecular stimulated increases in blood pressure, demonstrating the im- α α mechanism by which the DAPC imparts functionality to the 1D- portance of these essential GIPs for 1D-AR function in vivo (10). -
B1-Syntrophin Modulation by Mir-222 in Mdx Mice
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central b1-Syntrophin Modulation by miR-222 in mdx Mice Valeria De Arcangelis1, Filippo Serra1, Carlo Cogoni3, Elisabetta Vivarelli1, Lucia Monaco2*, Fabio Naro1,4 1 Department of Histology and Medical Embryology, University Sapienza, Rome, Italy, 2 Department of Physiology and Pharmacology, University Sapienza, Rome, Italy, 3 Department of Cellular Biotechnology and Ematology, University Sapienza, Rome, Italy, 4 IIM, Pavia, Italy Abstract Background: In mdx mice, the absence of dystrophin leads to the deficiency of other components of the dystrophin- glycoprotein complex (DAPC), making skeletal muscle fibers more susceptible to necrosis. The mechanisms involved in the disappearance of the DAPC are not completely understood. The muscles of mdx mice express normal amounts of mRNA for the DAPC components, thus suggesting post-transcriptional regulation. Methodology/Principal Findings: We investigated the hypothesis that DAPC reduction could be associated with the microRNA system. Among the possible microRNAs (miRs) found to be upregulated in the skeletal muscle tissue of mdx compared to wt mice, we demonstrated that miR-222 specifically binds to the 39-UTR of b1-syntrophin and participates in the downregulation of b1-syntrophin. In addition, we documented an altered regulation of the 39-UTR of b1-syntrophin in muscle tissue from dystrophic mice. Conclusion/Significance: These results show the importance of the microRNA system in the regulation of DAPC components in dystrophic muscle, and suggest a potential role of miRs in the pathophysiology of dystrophy. Citation: De Arcangelis V, Serra F, Cogoni C, Vivarelli E, Monaco L, et al. -
Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach
International Journal of Molecular Sciences Review Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach Diana Cimiotti 1,* , Heidi Budde 2, Roua Hassoun 2 and Kornelia Jaquet 2,* 1 Department of Clinical Pharmacology, Ruhr-University Bochum, 44801 Bochum, Germany 2 Experimental and Molecular Cardiology, St. Josef Hospital and BG Bergmannsheil, Clinics of the Ruhr-University Bochum, 44791 Bochum, Germany; [email protected] (H.B.); [email protected] (R.H.) * Correspondence: [email protected] (D.C.); [email protected] (K.J.); Tel.: +49-234-32-27639 (D.C.) Abstract: The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non- sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM. Keywords: cardiomyopathy; restrictive cardiomyopathy; pediatric; sarcomere; contractile dysfunc- tion; calcium; aggregation; gene expression 1. The Sarcomere The sarcomere as the substructure of myofibrils is the contractile unit of striated muscles i.e. skeletal and cardiac muscle (Figure1). It forms a symmetric unit with the Citation: Cimiotti, D.; Budde, H.; M-disc in the center and is bordered by the Z-discs. M-disc and Z-disc provide the anchors Hassoun, R.; Jaquet, K. Genetic for thin, thick and elastic filaments. The elastic filament is composed of the giant protein Restrictive Cardiomyopathy: Causes and Consequences—An Integrative titin spanning half the sarcomere. -
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.