DOCSLIB.ORG

Roles of ERK1/2 Signaling in LMNA-Cardiomyopathy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Roles of ERK1/2 Signaling in LMNA-Cardiomyopathy Roles of ERK1/2 signaling in LMNA‐cardiomyopathy A Dissertation Submitted in Partial Fulfilment of the Requirements for the Degree of “Doctor rerum naturalium (Dr. rer. nat.)” to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by Maria Chatzifrangkeskou Berlin, 2016 Supervisor: Prof. Petra Knaus Second examiner: Prof. Sigmar Stricker Date of the defense: 08/11/2016 Table of Contents Chapter 1 Introduction ................................................................................................................. 14 1.1 Nucleus, nuclear lamina and laminopathies ....................................................................... 14 1.1.1 Nuclear lamins .............................................................................................................. 15 1.1.2 Structure of lamins ....................................................................................................... 18 1.1.3 Posttranslational Processing and Modifications of the Nuclear Lamins ...................... 19 1.1.4 Lamin filament assembly and disassembly .................................................................. 19 1.1.5 Connections of A‐type lamins with other nuclear envelope proteins ......................... 20 1.1.6 Connections between nucleus and cytoskeleton ......................................................... 22 1.1.7 Laminopathies .............................................................................................................. 27 1.1.8 Pathophysiology ........................................................................................................... 33 1.1.9 Animal models .............................................................................................................. 34 1.1.10 Current therapeutic options for striated muscle laminopathies ............................... 37 1.1.11 Potential new treamtents........................................................................................... 37 1.1.12 Other therapeutic options .......................................................................................... 40 1.2 Actin..................................................................................................................................... 42 1.2.1 Nucleator proteins ........................................................................................................ 43 1.2.2 Profilin........................................................................................................................... 46 1.2.3 Capping protein (CP) ..................................................................................................... 47 1.2.4 Severing proteins .......................................................................................................... 47 1.2.5 Actin filaments in muscle ............................................................................................. 53 1.2.6 Regulation of sarcomeric actin filaments ..................................................................... 55 1.3 TGF‐β (Transforming growth factor‐β) superfamily signaling ............................................ 59 1.3.1 Non‐Smad signaling pathways ..................................................................................... 63 1.3.2 Role of TGF‐β in diseases .............................................................................................. 64 1.3.3 TGF‐β in fibrosis ............................................................................................................ 65 1.3.4 TGF‐β‐induction of connective tissue growth factor ................................................... 68 Chapter 2 Manuscripts .................................................................................................................. 71 Chapter 3 Discussion ................................................................................................................... 136 Chapter 4 Bibliography ............................................................................................................... 151 Chapter 5 Appendices ................................................................................................................. 175 5.1 Appendix I .......................................................................................................................... 176 5.2 Appendix II ......................................................................................................................... 181 Chapter 6 Acknowledgments ...................................................................................................... 188 4 | Page Table of figures Figure 1: The eukaryotic nucleus ……………………………………………………………………………………………….…………13 Figure 2: Schematic structure of lamin family members……………………………………………………………….………18 Figure 3: Schematic illustration of the LEM‐domain proteins……………………………………………………….………21 Figure 4: Schematic diagram of the nucleocytoskeleton interactions ………………………………………………....23 Figure 5: Domain structure of the four main nesprin isoforms……………………………………………………….…….24 Figure 6: Schematic representation of the two perinuclear actin structures: actin cap and TAN lines….27 Figure 7: Laminopathies affecting striated muscles……………………………………………………………………………...30 Figure 8: Morphological changes οf the heart in cardiomyopathy………………………………………………………..31 Figure 9: A simplified overview of MAPK pathways in mammals……………………………………………………..…...39 Figure 10: Schematic representation of the actin‐binding proteins (ABPs) that influence the actin treadmilling……………………………………………………………………………………………………………………………………………43 Figure 11: Arp2/3‐mediated actin nucleation………………………………………………………………………………..…….…44 Figure 12: Actin nucleation and elongation by the formin family proteins……………………………………….….…46 Figure 13: Actin nucleation by tandem monomer‐binding nucleators…………………………………………….……..46 Figure 14: Regulation of actin filament dynamics by ADF/cofilin, profiling, CAP, twinfilin and AIP1.……….49 Figure 15: Schematic overview of the ADF/cofilin kinases and phosphatases and their upstream regulators…………………………………………………………………………………………………………………………………………...….52 Figure 16: Schematic drawing of sarcomere structure and sarcomere‐binding proteins………………….….…54 Figure 17: Domains of tropomodulin (Tmod) and leiomodin (Lmod) proteins…………………………………..……57 Figure 18: Functional domains of the three Smads subfamilies ………………………………………………………..……60 Figure 19: Schematic illustration of myofibroblast transdifferentiation.......................................................61 Figure 20: Schematic representation of the TGF‐β signaling pathway …………………………..……………………....66 Figure 21: The TGF–TAK1 pathway………………………………………………………………………………….…………….……..…68 Figure 22: Hypothetical model of increased TGF‐β signaling LmnaH222P/H222P mice……………….………….…….138 Figure 23: MRTF‐SRF axis………………………………………………………………………………………………………….……………144 Figure 24: Models of how abnormalities of A‐type lamins may lead to hyperactivation of ERK1/2…... ..146 Figure 25: Schematic representation of the data obtained during this thesis. ………………………………….……148 5 | Page Abbreviations ACE, angiotensin II converting enzyme EDMD, Emery Dreifuss muscular dystrophy ADF, actin-depolymerizing factor EF, ejection fraction ALK, activin receptor-like kinases ERK, extracellular sign-regulated kinases ALS, amyotrophic lateral sclerosis ERK1/2 extracellular signal-regulated kinase 1/2 AMH/MIS, anti-Müllerian hormone/Müllerian ESCs, embryonic stem cells inhibiting substance F-actin, filamentous actin AP-1 activator protein-1 FAK, focal adhesion kinase ATF-2, activated transcription factor-2 FH1, formin-homology 1; aWRN, atypical Werner syndrome FH2, formin-homology 2 BAF, Barrier to Autointegration Factor FPLD, familial lipodystrophy of Dunnigan type BMP, bone-morphogenetic protein FR, fractional shortening CaMKII, Ca2+/calmodulin-dependent protein FRAP, fluorescence-recovery after photobleaching kinase II, FS, Fractional shortening CBD, chromatin binding domain G-actin, globular actin Cdc42, cell division cycle 42, GDF, growth and differentiation factors family CDK, cyclin dependent kinases GPCR, G-protein-coupled receptors Cdk1, cyclin dependent kinase-1 GSK, Glycogen synthase kinase 3 CH, Calponin-homology domain HGPS, Hutchinson-Gilford progeria syndrome CIN, chronophin HP1, heterochromatin-associated protein-1 CMD, Congenital muscular dystrophy ICD, intracardiac cardioverter defibrillator CMT2B1, Charcot-Marie Tooth type 2B1 ICMT, isoprenylcysteine carboxyl Cobl, cordon-bleu methyltransferase Co-Smads, common Smads, INM, inner nuclear membrane CP, capping protein iPSCs, induced pluripotent stem cells CTGF, Connective Tissue Growth Factor I-Smads, inhibitory Smads, DAG, diaglycerol JNK, c-Jun N terminal kinase DCM, dilated cardiomyopathy JNK, c-JUN N-terminal kinase DCM-CD, dilated cardiomyopathy with KASH, Klarsicht/ANC-1/Syne-1 homologue conduction system disease LAD, lamina-associated domains ECG, electrocardiogram LAP, lamina-associated polypeptide ECM, extracellular matrix LAP, latency-associated peptide 6 | Page LBR, lamin B receptor PP1, protein phosphatase 1 LEM, Lamina-associated polypeptide, Emerin PP2A, protein phosphatase 2A and-MAN1 Rce1, Ras-converting enzyme 1 LGMD1B, limb-girdle muscular dystrophy type ROCK, RHO-associated coiled-coil-containing 1B protein kinase LIMK, Lin-11/Isl-1/Mec-3 kinase R-Smads, regulatory Smads LINC, LInker of Nucleoskeleton and RTK, receptor tyrosine kinase Cytoskeleton RTK, receptors with intrinsic tyrosine kinase Lmod, leiomodin activity LV, left ventricule
Load more

Recommended publications
  • Supplemental Figure 1. Vimentin
    Double mutant specific genes Transcript gene_assignment Gene Symbol RefSeq FDR Fold- FDR Fold- FDR Fold- ID (single vs. Change (double Change (double Change wt) (single vs. wt) (double vs. single) (double vs. wt) vs. wt) vs. single) 10485013 BC085239 // 1110051M20Rik // RIKEN cDNA 1110051M20 gene // 2 E1 // 228356 /// NM 1110051M20Ri BC085239 0.164013 -1.38517 0.0345128 -2.24228 0.154535 -1.61877 k 10358717 NM_197990 // 1700025G04Rik // RIKEN cDNA 1700025G04 gene // 1 G2 // 69399 /// BC 1700025G04Rik NM_197990 0.142593 -1.37878 0.0212926 -3.13385 0.093068 -2.27291 10358713 NM_197990 // 1700025G04Rik // RIKEN cDNA 1700025G04 gene // 1 G2 // 69399 1700025G04Rik NM_197990 0.0655213 -1.71563 0.0222468 -2.32498 0.166843 -1.35517 10481312 NM_027283 // 1700026L06Rik // RIKEN cDNA 1700026L06 gene // 2 A3 // 69987 /// EN 1700026L06Rik NM_027283 0.0503754 -1.46385 0.0140999 -2.19537 0.0825609 -1.49972 10351465 BC150846 // 1700084C01Rik // RIKEN cDNA 1700084C01 gene // 1 H3 // 78465 /// NM_ 1700084C01Rik BC150846 0.107391 -1.5916 0.0385418 -2.05801 0.295457 -1.29305 10569654 AK007416 // 1810010D01Rik // RIKEN cDNA 1810010D01 gene // 7 F5 // 381935 /// XR 1810010D01Rik AK007416 0.145576 1.69432 0.0476957 2.51662 0.288571 1.48533 10508883 NM_001083916 // 1810019J16Rik // RIKEN cDNA 1810019J16 gene // 4 D2.3 // 69073 / 1810019J16Rik NM_001083916 0.0533206 1.57139 0.0145433 2.56417 0.0836674 1.63179 10585282 ENSMUST00000050829 // 2010007H06Rik // RIKEN cDNA 2010007H06 gene // --- // 6984 2010007H06Rik ENSMUST00000050829 0.129914 -1.71998 0.0434862 -2.51672
    [Show full text]
  • Decreased Expression of Profilin 2 in Oral Squamous Cell Carcinoma and Its Clinicopathological Implications
    ONCOLOGY REPORTS 26: 813-823, 2011 Decreased expression of profilin 2 in oral squamous cell carcinoma and its clinicopathological implications C.Y. MA1,2, C.P. ZHANG1,2, L.P. ZHONG1,2, H.Y. PAN1,2, W.T. CHEN1,2, L.Z. WANG3, O.W. ANDREW4, T. JI1 and W. HAN1,2 1Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, College of Stomatology; 2Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology; 3Department of Oral Pathology, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China; 4Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, Singapore 119074, Singapore Received February 8, 2011; Accepted April 11, 2011 DOI: 10.3892/or.2011.1365 Abstract. Profilins are small proteins essential for many clinical and pathological significance. In conclusion, PFN2 normal cellular dynamics and constitute one of the crucial can be utilized as both a potential suppressor marker and a components of actin-based cellular motility. Several recent prognostic protein for OSCC. The function of PFN2 may be to studies have implicated a role for the profilin (PFN) family in regulate the N-WASP/Arp2/3 signaling pathway. cancer pathogenesis and progression. However, their expression and promising functions are largely unknown in oral squamous Introduction cell carcinoma (OSCC). In this study, we analyzed the correlation between PFN1 and PFN2 expression in vitro and Oral squamous cell carcinoma (OSCC) is a significant public in vivo. The protein expression levels were roughly compared health problem with >300,000 new cases being diagnosed between cell lines (HIOEC, HB96) with the employment of annually worldwide (1).
    [Show full text]
  • Impairments in Contractility and Cytoskeletal Organisation Cause Nuclear Defects in Nemaline Myopathy
    bioRxiv preprint doi: https://doi.org/10.1101/518522; this version posted January 28, 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. Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy Jacob A Ross1, Yotam Levy1, Michela Ripolone2, Justin S Kolb3, Mark Turmaine4, Mark Holt5, Maurizio Moggio2, Chiara Fiorillo6, Johan Lindqvist3, Nicolas Figeac5, Peter S Zammit5, Heinz Jungbluth5,7,8, John Vissing9, Nanna Witting9, Henk Granzier3, Edmar Zanoteli10, Edna C Hardeman11, Carina Wallgren- Pettersson12, Julien Ochala1,5. 1. Centre for Human & Applied Physiological Sciences, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, Guy’s Campus, King’s College London, SE1 1UL, UK 2. Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy 3. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, 85721, USA 4. Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK 5. Randall Centre for Cell and Molecular Biophysics, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, Guy’s Campus, King’s College London, SE1 1UL, UK 6. Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa and Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa, Italy 7. Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St Thomas' Hospital National Health Service Foundation Trust, London, SE1 9RT, UK 8. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, SE1 1UL, UK 9.
    [Show full text]
  • Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth
    International Journal of Molecular Sciences Article Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth Daniel J. Owens 1,2 , Julien Messéant 1, Sophie Moog 3, Mark Viggars 2, Arnaud Ferry 1,4, Kamel Mamchaoui 1,5, Emmanuelle Lacène 5 , Norma Roméro 5,6, Astrid Brull 1 , Gisèle Bonne 1 , Gillian Butler-Browne 1 and Catherine Coirault 1,* 1 Center for Research in Myology, Sorbonne Université, INSERM UMRS_974, 75013 Paris, France; [email protected] (D.J.O.); [email protected] (J.M.); [email protected] (A.F.); [email protected] (K.M.); [email protected] (A.B.); [email protected] (G.B.); [email protected] (G.B.-B.) 2 Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, UK; [email protected] 3 Inovarion, 75005 Paris, France; [email protected] 4 Université de Paris, 75006 Paris, France 5 Neuromuscular Morphology Unit, Institute of Myology, Pitié-Salpêtrière Hospital, 75013 Paris, France; [email protected] (E.L.); [email protected] (N.R.) 6 APHP, Reference Center for Neuromuscular Disorders, Pitié-Salpêtrière Hospital, Institute of Myology, 75013 Paris, France * Correspondence: [email protected]; Tel.: +33-1-1-4216-5708 Abstract: Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular Citation: Owens, D.J.; Messéant, J.; dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD).
    [Show full text]
  • Assembly and Maintenance of Sarcomere Thin Filaments and Associated Diseases
    International Journal of Molecular Sciences Review Assembly and Maintenance of Sarcomere Thin Filaments and Associated Diseases Kendal Prill and John F. Dawson * Centre for Cardiovascular Investigations, Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada; [email protected] * Correspondence: [email protected] Received: 17 December 2019; Accepted: 12 January 2020; Published: 15 January 2020 Abstract: Sarcomere assembly and maintenance are essential physiological processes required for cardiac and skeletal muscle function and organism mobility. Over decades of research, components of the sarcomere and factors involved in the formation and maintenance of this contractile unit have been identified. Although we have a general understanding of sarcomere assembly and maintenance, much less is known about the development of the thin filaments and associated factors within the sarcomere. In the last decade, advancements in medical intervention and genome sequencing have uncovered patients with novel mutations in sarcomere thin filaments. Pairing this sequencing with reverse genetics and the ability to generate patient avatars in model organisms has begun to deepen our understanding of sarcomere thin filament development. In this review, we provide a summary of recent findings regarding sarcomere assembly, maintenance, and disease with respect to thin filaments, building on the previous knowledge in the field. We highlight debated and unknown areas within these processes to clearly define open research questions. Keywords: sarcomere assembly; sarcomere maintenance; sarcomere thin filaments; thin filament assembly; thin filament maintenance; thin filament turnover; actin turnover; chaperone; sarcomere; myopathy 1. Introduction Striated muscle requires the coordination of hundreds of proteins not only for cellular function but also for assembly of the contractile sarcomere units within the myofibril.
    [Show full text]
  • ARVC-Variants.Pdf
    Updated gene list responsible for ARVC/D pathology Subtype Gene Location Reference ARVC1 TGFB3 14q24.3 Beffagna G, Occhi G, Nava A, et al. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res. 2005;65:366–73. ARVC2 RYR2 1q43 Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001;10:189–94. ARVC3 Unknown 14q12-q22 Severini GM, Krajinovic M, Pinamonti B, et al. A new locus for arrhythmogenic right ventricular dysplasia on the long arm of chromosome 14. Genomics. 1996;31:193–200. ARVC4 TTN 2q32.1-q32.3 Taylor M, Graw S, Sinagra G, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation. 2011;124:876–85. ARVC5 TMEM43 3p25.1 Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:809–21. ARVC6 Unknown 10p14-p12 Li D, Ahmad F, Gardner MJ, et al. The locus of a novel gene responsible for arrhythmogenic right- ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p12-p14. Am J Hum Genet. 2000;66:148–56. ARVC7 DES 2q35 Klauke B, Kossmann S, Gaertner A, et al. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum Mol Genet. 2010;19:4595–607.
    [Show full text]
  • 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.
    [Show full text]
  • Genome-Wide Analyses Identify KIF5A As a Novel ALS Gene
    This is a repository copy of Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/129590/ Version: Accepted Version Article: Nicolas, A, Kenna, KP, Renton, AE et al. (210 more authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97 (6). 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027 Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Genome-wide Analyses Identify KIF5A as a Novel ALS Gene Aude Nicolas1,2, Kevin P. Kenna2,3, Alan E. Renton2,4,5, Nicola Ticozzi2,6,7, Faraz Faghri2,8,9, Ruth Chia1,2, Janice A. Dominov10, Brendan J. Kenna3, Mike A. Nalls8,11, Pamela Keagle3, Alberto M. Rivera1, Wouter van Rheenen12, Natalie A. Murphy1, Joke J.F.A. van Vugt13, Joshua T. Geiger14, Rick A. Van der Spek13, Hannah A. Pliner1, Shankaracharya3, Bradley N.
    [Show full text]
  • Nuclear Matrix
    Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective Pierre Cau, Claire Navarro, Karim Harhouri, Patrice Roll, Sabine Sigaudy, Elise Kaspi, Sophie Perrin, Annachiara de Sandre-Giovannoli, Nicolas Lévy To cite this version: Pierre Cau, Claire Navarro, Karim Harhouri, Patrice Roll, Sabine Sigaudy, et al.. Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective. Seminars in Cell and Developmental Biology, Elsevier, 2014, 29, pp.125-147. 10.1016/j.semcdb.2014.03.021. hal-01646524 HAL Id: hal-01646524 https://hal-amu.archives-ouvertes.fr/hal-01646524 Submitted on 20 Dec 2017 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. Review Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective Pierre Cau a,b,c,∗, Claire Navarro a,b,1, Karim Harhouri a,b,1, Patrice Roll a,b,c,1,2, Sabine Sigaudy a,b,d,1,3, Elise Kaspi a,b,c,1,2, Sophie Perrin a,b,1, Annachiara De Sandre-Giovannoli a,b,d,1,3, Nicolas Lévy a,b,d,∗∗ a Aix-Marseille
    [Show full text]
  • Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation Omotola F. Omotade1,3, Yanfang Rui1,3, Wenliang Lei1,3, Kuai Yu1, H. Criss Hartzell1, Velia M. Fowler4 and James Q. Zheng1,2,3 1Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322. 2Department of Neurology 3Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322. 4Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037 DOI: 10.1523/JNEUROSCI.3325-17.2018 Received: 22 November 2017 Revised: 25 September 2018 Accepted: 2 October 2018 Published: 9 October 2018 Author contributions: O.F.O. and J.Q.Z. designed research; O.F.O., Y.R., W.L., and K.Y. performed research; O.F.O. and J.Q.Z. analyzed data; O.F.O. and J.Q.Z. wrote the paper; Y.R., H.C.H., V.M.F., and J.Q.Z. edited the paper; V.M.F. contributed unpublished reagents/analytic tools. Conflict of Interest: The authors declare no competing financial interests. This research project was supported in part by research grants from National Institutes of Health to JQZ (GM083889, MH104632, and MH108025), OFO (5F31NS092437-03), VMF (EY017724) and HCH (EY014852, AR067786), as well as by the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities grant (5P30NS055077). We would like to thank Dr. Kenneth Myers for his technical expertise and help throughout the project. We also thank Drs.
    [Show full text]
  • Nuclear Titin Interacts with A- and B-Type Lamins in Vitro and in Vivo
    Research Article 239 Nuclear Titin interacts with A- and B-type lamins in vitro and in vivo Michael S. Zastrow1,*, Denise B. Flaherty2‡, Guy M. Benian2 and Katherine L. Wilson1,§ 1Department of Cell Biology, The Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USA 2Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, GA 30332, USA *Present address: Department of Developmental Biology, Stanford University School of Medicine, Beckman Center, B300, 279 Campus Drive, Stanford, CA 94305, USA ‡Department of Biology, Eckerd College, SHB 105, 4200 54th Ave, St Petersburg, FL 33711, USA §Author for correspondence (e-mail: [email protected]) Accepted 4 October 2005 Journal of Cell Science 119, 239-249 Published by The Company of Biologists 2006 doi:10.1242/jcs.02728 Summary Lamins form structural filaments in the nucleus. Mutations lamin-downregulated [lmn-1(RNAi)] embryos, Ce-titin was in A-type lamins cause muscular dystrophy, undetectable at the nuclear envelope suggesting its cardiomyopathy and other diseases, including progeroid localization or stability requires Ce-lamin. In human cells syndromes. To identify new binding partners for lamin A, (HeLa), antibodies against the titin-specific domain M-is6 we carried out a two-hybrid screen with a human skeletal- gave both diffuse and punctate intranuclear staining by muscle cDNA library, using the Ig-fold domain of lamin A indirect immunofluorescence, and recognized at least three as bait. The C-terminal region of titin was recovered twice. bands larger than 1 MDa in immunoblots of isolated HeLa Previous investigators showed that nuclear isoforms of titin nuclei.
    [Show full text]
  • Lamin A/C Cardiomyopathy: Implications for Treatment
    Current Cardiology Reports (2019) 21:160 https://doi.org/10.1007/s11886-019-1224-7 MYOCARDIAL DISEASE (A ABBATE AND G SINAGRA, SECTION EDITORS) Lamin A/C Cardiomyopathy: Implications for Treatment Suet Nee Chen1 & Orfeo Sbaizero1,2 & Matthew R. G. Taylor1 & Luisa Mestroni1 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The purpose of this review is to provide an update on lamin A/C (LMNA)-related cardiomyopathy and discuss the current recommendations and progress in the management of this disease. LMNA-related cardiomyopathy, an inherited autosomal dominant disease, is one of the most common causes of dilated cardiomyopathy and is characterized by steady progression toward heart failure and high risks of arrhythmias and sudden cardiac death. Recent Findings We discuss recent advances in the understanding of the molecular mechanisms of the disease including altered cell biomechanics, which may represent novel therapeutic targets to advance the current management approach, which relies on standard heart failure recommendations. Future therapeutic approaches include repurposed molecularly directed drugs, siRNA- based gene silencing, and genome editing. Summary LMNA-related cardiomyopathy is the focus of active in vitro and in vivo research, which is expected to generate novel biomarkers and identify new therapeutic targets. LMNA-related cardiomyopathy trials are currently underway. Keywords Lamin A/C gene . Laminopathy . Heart failure . Arrhythmias . Mechanotransduction . P53 . CRISPR–Cas9 therapy Introduction functions, including maintaining nuclear structural integrity, regulating gene expression, mechanosensing, and Mutations in the lamin A/C gene (LMNA)causelaminopathies, mechanotransduction through the lamina-associated proteins a heterogeneous group of inherited disorders including muscu- [6–11].
    [Show full text]