Dystrophin Complex Functions As a Scaffold for Signalling Proteins☆
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
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. -
Development of a High-Throughput Screen to Identify Small Molecule Enhancers of Sarcospan for the Treatment of Duchenne Muscular Dystrophy
UCLA UCLA Previously Published Works Title Development of a high-throughput screen to identify small molecule enhancers of sarcospan for the treatment of Duchenne muscular dystrophy. Permalink https://escholarship.org/uc/item/85z6k8t7 Journal Skeletal muscle, 9(1) ISSN 2044-5040 Authors Shu, Cynthia Kaxon-Rupp, Ariana N Collado, Judd R et al. Publication Date 2019-12-12 DOI 10.1186/s13395-019-0218-x Peer reviewed eScholarship.org Powered by the California Digital Library University of California Shu et al. Skeletal Muscle (2019) 9:32 https://doi.org/10.1186/s13395-019-0218-x RESEARCH Open Access Development of a high-throughput screen to identify small molecule enhancers of sarcospan for the treatment of Duchenne muscular dystrophy Cynthia Shu1,2,3, Ariana N. Kaxon-Rupp2, Judd R. Collado2, Robert Damoiseaux4,5 and Rachelle H. Crosbie1,2,3,6* Abstract Background: Duchenne muscular dystrophy (DMD) is caused by loss of sarcolemma connection to the extracellular matrix. Transgenic overexpression of the transmembrane protein sarcospan (SSPN) in the DMD mdx mouse model significantly reduces disease pathology by restoring membrane adhesion. Identifying SSPN-based therapies has the potential to benefit patients with DMD and other forms of muscular dystrophies caused by deficits in muscle cell adhesion. Methods: Standard cloning methods were used to generate C2C12 myoblasts stably transfected with a fluorescence reporter for human SSPN promoter activity. Assay development and screening were performed in a core facility using liquid handlers and imaging systems specialized for use with a 384-well microplate format. Drug-treated cells were analyzed for target gene expression using quantitative PCR and target protein expression using immunoblotting. -
Ryanodine Receptors Are Part of the Myospryn Complex in Cardiac Muscle Received: 10 March 2017 Matthew A
www.nature.com/scientificreports OPEN Ryanodine receptors are part of the myospryn complex in cardiac muscle Received: 10 March 2017 Matthew A. Benson1, Caroline L. Tinsley2, Adrian J. Waite 2, Francesca A. Carlisle2, Steve M. Accepted: 12 June 2017 M. Sweet3, Elisabeth Ehler4, Christopher H. George5, F. Anthony Lai5,6, Enca Martin-Rendon7 Published online: 24 July 2017 & Derek J. Blake 2 The Cardiomyopathy–associated gene 5 (Cmya5) encodes myospryn, a large tripartite motif (TRIM)- related protein found predominantly in cardiac and skeletal muscle. Cmya5 is an expression biomarker for a number of diseases afecting striated muscle and may also be a schizophrenia risk gene. To further understand the function of myospryn in striated muscle, we searched for additional myospryn paralogs. Here we identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of myospryn. Cmya5 and Fsd2 appear to have originated by a chromosomal duplication and are found within evolutionarily-conserved gene clusters on diferent chromosomes. Using immunoafnity purifcation and mass spectrometry we show that minispryn co-purifes with myospryn and the major cardiac ryanodine receptor (RyR2) from heart. Accordingly, myospryn, minispryn and RyR2 co-localise at the junctional sarcoplasmic reticulum of isolated cardiomyocytes. Myospryn redistributes RyR2 into clusters when co-expressed in heterologous cells whereas minispryn lacks this activity. Together these data suggest a novel role for the myospryn complex in the assembly of ryanodine receptor clusters in striated muscle. Te unique cytoskeletal organisation of striated muscle is dependent upon the formation of specialised interac- tions between proteins that have both structural and signalling functions1. -
Dystrobrevin Alpha Gene Is a Direct Target of the Vitamin D Receptor in Muscle
64 3 Journal of Molecular M K Tsoumpra et al. Upregulation of dystrobrevin by 64:3 195–208 Endocrinology calcitriol RESEARCH Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle Maria K Tsoumpra1, Shun Sawatsubashi2, Michihiro Imamura1, Seiji Fukumoto2, Shin’ichi Takeda1, Toshio Matsumoto2 and Yoshitsugu Aoki1 1Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan 2Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan Correspondence should be addressed to S Fukumoto: [email protected] Abstract The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its Key Words tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which f vitamin D functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response f muscle elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle f gene regulation cells occurs concomitantly with transcriptional regulation of key myogenic factors upon f receptor binding VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1–50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. -
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. -
The Neurotransmitter Released at the Neuromuscular Junction Is
The Neurotransmitter Released At The Neuromuscular Junction Is Towney congeals his bibbers manipulate jocular, but cash-and-carry Winfred never extravasating so malcontentedly. Is Norton always dipetalous and unworn when guzzled some admeasurement very untidily and adversely? Busty Dominic overexcited some close and jemmying his galluses so nautically! Hiw are four nlgs are working memory, sv hubs depending on the specific to the neurotransmitter released neuromuscular junction at institutions across brain The energy is delivered in a fractional manner. Smooth muscle NMJ is formed between the autonomic nerve fibers that branch diffusely on strength muscle in form diffuse junctions. In an intact brain, volume was observed that Cac density at AZs is indeed strongly correlated with Pr. Chemical synapses involve the transmission of chemical information from one cell as the next. Currents through the fusion pore that forms during exocytosis of a secretory vesicle. If you order something abusive or that does not lessen with surrender terms or guidelines please flag it as inappropriate. Ach in the presynaptic protein in the active secretors of the released. You can login by using one alongside your existing accounts. Many drugs and anesthetic agents also affect neuromuscular junction and impulse transmission to inside their effects. The chemical must be present within a neuron. Another route for tetanus is lockjaw, respectively, the calcium rushes out of newly opened gates. In our data presented at multiple neurotransmitters are commonly performed by abnormal nmj but the neurotransmitter released at is the neuromuscular junction, it will fail to propagate from another power stroke can have qualitatively distinct categories reflective of the resultant of development. -
Reviewreview Duchenne Muscular Dystrophy and Dystrophin: Pathogenesis and Opportunities for Treatment Third in Molecular Medicine Review Series Kristen J
reviewreview Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment Third in Molecular Medicine Review Series Kristen J. Nowak† & Kay E. Davies+ MRC Functional Genetics Unit, University of Oxford, UK Duchenne muscular dystrophy (DMD) is caused by mutations in protein. Becker muscular dystrophy (BMD; OMIM 300376)—a the gene that encodes the 427-kDa cytoskeletal protein dys- much milder form of the disease—is caused by a reduction in the trophin. Increased knowledge of the function of dystrophin and amount, or alteration in the size, of the dystrophin protein. The its role in muscle has led to a greater understanding of the high incidence of sporadic cases of DMD (1 in 10,000 sperm or pathogenesis of DMD. This, together with advances in the eggs) means that genetic screening will never eliminate this dis- genetic toolkit of the molecular biologist, are leading to many ease, so an effective therapy is highly desirable. This review sum- different approaches to treatment. Gene therapy can be marizes our understanding of the disease and the strategies that are achieved using plasmids or viruses, mutations can be corrected being developed for an effective treatment (Fig 1). using chimaeraplasts and short DNA fragments, exon skipping of mutations can be induced using oligonucleotides and Pathogenesis readthrough of nonsense mutations can be achieved using Dystrophin has a major structural role in muscle as it links the aminoglycoside antibiotics. Blocking the proteasome degrada- internal cytoskeleton to the extracellular matrix. The amino-terminus tion pathway can stabilize any truncated dystrophin protein, of dystrophin binds to F-actin and the carboxyl terminus to the and upregulation of other proteins can also prevent the dys- dystrophin-associated protein complex (DAPC) at the sarcolemma trophic process. -
Governs the Making of Photocopies Or Other Reproductions of Copyrighted Materials
Warning Concerning Copyright Restrictions The Copyright Law of the United States (Title 17, United States Code) governs the making of photocopies or other reproductions of copyrighted materials. Under certain conditions specified in the law, libraries and archives are authorized to furnish a photocopy or other reproduction. One of these specified conditions is that the photocopy or reproduction is not to be used for any purpose other than private study, scholarship, or research. If electronic transmission of reserve material is used for purposes in excess of what constitutes "fair use," that user may be liable for copyright infringement. University of Nevada, Reno The Role of Utrophin, Sarcospan, and Glycosyltransferase Activity in the Pathogenesis of Duchenne Muscular Dystrophy and a Representative Case Study A thesis submitted in partial fulfillment of the requirements for the degree of Bachelor of Science in Biochemistry & Molecular Biology by Susan T. Alaei Josh Baker, Ph.D., Thesis Advisor May, 2013 UNIVERSITY OF NEVADA THE HONORS PROGRAM RENO We recommend that the thesis prepared under our supervision by Susan T. Alaei entitled The Role of Utrophin, Sarcospan, and Glycosyltransferase Activity in the Pathogenesis of Duchenne Muscular Dystrophy and a Representative Case Study be accepted in partial fulfillment of the requirements for the degree of Bachelor of Science in Biochemistry & Molecular Biology ______________________________________________ Josh Baker, Ph.D., Thesis Advisor ______________________________________________ Tamara Valentine, Ph.D., Director, Honors Program May 2013 i Abstract Duchenne Muscular Dystrophy is a degenerative muscle disease that is characterized by the breakdown of skeletal muscle as a result of membrane instability. A mutation in the dystrophin gene, one of the largest gene in the human genome, results in a complete lack of dystrophin in the membrane of skeletal muscle cells. -
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. -
Sarcospan-Dependent Akt Activation Is Required for Utrophin Expression and Muscle Regeneration
JCB: Article Sarcospan-dependent Akt activation is required for utrophin expression and muscle regeneration Jamie L. Marshall,1 Johan Holmberg,1 Eric Chou,1 Amber C. Ocampo,1 Jennifer Oh,1 Joy Lee,1 Angela K. Peter,1 Paul T. Martin,3,4 and Rachelle H. Crosbie-Watson1,2 1Department of Integrative Biology and Physiology and 2Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095 3Center for Gene Therapy, The Research Institute, Nationwide Children’s Hospital, and 4Department of Pediatrics, Ohio State University College of Medicine and College of Public Health, Columbus, OH 43205 trophin is normally confined to the neuromus- sarcolemma. SSPN-null mice displayed delayed differen- cular junction (NMJ) in adult muscle and par- tiation after CTX injury caused by loss of utrophin and Akt U tially compensates for the loss of dystrophin in signaling. Treatment of SSPN-null mice with viral Akt mdx mice. We show that Akt signaling and utrophin increased utrophin and restored muscle repair after in- levels were diminished in sarcospan (SSPN)-deficient jury, revealing an important role for the SSPN-Akt-utro- muscle. By creating several transgenic and knockout phin signaling axis in regeneration. SSPN improved cell mice, we demonstrate that SSPN regulates Akt signal- surface expression of utrophin by increasing transportation ing to control utrophin expression. SSPN determined of utrophin and DG from endoplasmic reticulum/Golgi -dystroglycan (-DG) glycosylation by affecting levels membranes. Our experiments reveal functions of utro- of the NMJ-specific glycosyltransferase Galgt2. After phin in regeneration and new pathways that regulate cardiotoxin (CTX) injury, regenerating myofibers ex- utrophin expression at the cell surface. -
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. -
Genomics of Inherited Bone Marrow Failure and Myelodysplasia Michael
Genomics of inherited bone marrow failure and myelodysplasia Michael Yu Zhang A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2015 Reading Committee: Mary-Claire King, Chair Akiko Shimamura Marshall Horwitz Program Authorized to Offer Degree: Molecular and Cellular Biology 1 ©Copyright 2015 Michael Yu Zhang 2 University of Washington ABSTRACT Genomics of inherited bone marrow failure and myelodysplasia Michael Yu Zhang Chair of the Supervisory Committee: Professor Mary-Claire King Department of Medicine (Medical Genetics) and Genome Sciences Bone marrow failure and myelodysplastic syndromes (BMF/MDS) are disorders of impaired blood cell production with increased leukemia risk. BMF/MDS may be acquired or inherited, a distinction critical for treatment selection. Currently, diagnosis of these inherited syndromes is based on clinical history, family history, and laboratory studies, which directs the ordering of genetic tests on a gene-by-gene basis. However, despite extensive clinical workup and serial genetic testing, many cases remain unexplained. We sought to define the genetic etiology and pathophysiology of unclassified bone marrow failure and myelodysplastic syndromes. First, to determine the extent to which patients remained undiagnosed due to atypical or cryptic presentations of known inherited BMF/MDS, we developed a massively-parallel, next- generation DNA sequencing assay to simultaneously screen for mutations in 85 BMF/MDS genes. Querying 71 pediatric and adult patients with unclassified BMF/MDS using this assay revealed 8 (11%) patients with constitutional, pathogenic mutations in GATA2 , RUNX1 , DKC1 , or LIG4 . All eight patients lacked classic features or laboratory findings for their syndromes.