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Exploring the Mitochondrial Function in Muscle and Molecular Dysregulation in Cerebellum in a Mouse Model for ARCA2, a Recessive

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Exploring the mitochondrial function in muscle and molecular dysregulation in cerebellum in a mouse model for ARCA2, a recessive ataxia with coenzyme Q10 deficiency Tiphaine Jaeg To cite this version: Tiphaine Jaeg. Exploring the mitochondrial function in muscle and molecular dysregulation in cere- bellum in a mouse model for ARCA2, a recessive ataxia with coenzyme Q10 deficiency. Neurobiology. Université de Strasbourg, 2017. English. NNT : 2017STRAJ082. tel-02003420 HAL Id: tel-02003420 https://tel.archives-ouvertes.fr/tel-02003420 Submitted on 1 Feb 2019 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. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE Institut de Génétique et Biologie Moléculaire et Cellulaire THÈSE présentée par : Tiphaine JAEG soutenue le : 03 octobre 2017 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/ Spécialité : Aspects moléculaires et cellulaires de la biologie Exploring the mitochondrial function in muscle and molecular dysregulation in cerebellum in a mouse model for ARCA2, a recessive ataxia with coenzyme Q10 deficiency THÈSE dirigée par : Dr PUCCIO Hélène Directrice de Recherche, IGBMC, Inserm U964, UMR 7104 CNRS, Université de Strasbourg RAPPORTEURS : Dr RÖTIG Agnès Directrice de Recherche, Institut Imagine, Inserm U1163 Dr QUINZII Catarina MD PhD, Assistant Professor, Columbia University Medical Center AUTRES MEMBRES DU JURY : Dr DUPUIS Luc Directeur de recherche, Inserm U1118, Université de Strasbourg MEMBRE INVITE Dr ISOPE Philippe Directeur de recherche, INCI, CNRS UPR 3212 Try to leave this world a little better than you found it and, when your turn comes to die, you can die happy in feeling that at any rate you have not wasted your time but have done your best Robert Baden‐Powell Acknowledgements I would like to dedicate these first line to Hélène Puccio, my PhD supervisor who accepted to host me in her lab starting from September 2013. Thanks for the freedom you gave me and all what I learned during these four years. Thanks to the Dr. Luc Dupuis, Philippe Isope and Yvon Trottier who helped us decide what should be the best path to pursue with. Also, a big thank for having evaluated my work at key moments of my thesis which helped me go further. I would like to thank the Dr. Agnès Rötig, Catarina Quinzii, Luc Dupuis and Philippe Isope for having accepted to evaluate my work, and taken part of their time to read through this manuscript. I thank Laurence, for the help she has provided me for experiments. Thank for having explained me patiently some assays, how to handle mice, how to deal with mice colonies and how to build cohorts. Thanks also for having accepted to generate and genotype so many mice for the purpose of my experiments. I’m really grateful. Thanks to Floriana, Leïla and Pankaj with whom I worked with, trying to unravel the cause of ARCA2 and who have cheered me up and shared doubts, questions, ideas about this hard but fascinating project. Thanks to all the lab members, for the nice discussions we had and all what I learned from you! For sharing protocols, benches, and brainstorming for new experiments and troubleshooting. Thanks to Nadège and Aurélie, for their kindness and benevolence. You laugh and smiles each day made my everyday life so much nicer! I also greatly appreciated all the little things you did to make my life easier and to help me take decisions for certain experiments. I now have to dedicate an entire paragraph to Charline, so here you are ;‐p! Thanks for having shared the back of the lab with me. I will never forget how we cheered each other up, and for our numerous discussions. Thanks for having been there, with me, late in the lab and for all our debates and brainstorming about protocols, new experimental design, publications and so on. Thanks for having wondered about me and make me realize I needed to slow down at some points to be able to achieve this PhD. Thanks for the numerous giggles that made life in the lab so much nicer and gave me energy to work more and persevere. And a simple big thank for your smiles. Samantha and Arielle, this PhD would not have been the same without you! We shared our doubts, rejoice, questions… You were always around, even late in the cell culture room or the lab, sharing chocolate or motivation to cheer up. I will never forget these precious moments so thanks! Thanks also to Angélique, Francesca, Florent, Aurore, Léa, Mélanie, with whom I sometimes ate, and often met in the corridors, thanks for the long discussions, your advices and tips! And thanks for your friendship. Thanks to the IGBMC platforms and services for all the help provided. Thanks to Nadia, Jean‐Luc and Josiane for the electron microscopy. Thanks to Betty, Marion and all the girls from the cell culture facility. A big thanks to Marc, Marcel and Yves who helped me with microscopy. A huge thanks to Pascal for his patience and time, explaining microscopy, building macros to help the little PhD student I was. 1 Thanks also to Frédéric Doussau, for teaching me how to perform organotypic cultures, immunofluorescence with them, and all the nice ideas he shared. Thanks to Paulo and Francine, who simplified our PhD lifes. A special thanks to Paulo for having supervised the organization of the PhD retreat. And thanks to Arielle, Samantha, Damola, Hichem, Federica, Tajith and Tiago for the nice PhD retreat we have built up. Merci à tous les Openlabistes, avec qui j’ai partagé cette belle aventure. Je vous suis reconnaissante pour les parfois longues discussions dans la voiture, direction les interventions, à refaire le monde et surtout la biologie, à essayer de tourner et retourner les problèmes sur lesquels nous bloquions pour nos sujets de thèse. Merci pour vos remarques et idées ! Et merci pour les bons moments passés à expliquer la science simplement. Merci à ma famille et tous mes amis et qui m’ont encouragé et soutenu tout au long de cette thèse. Merci à Maëlyne, Soléane, Auxence et Isaure, de m’avoir fait voir la beauté de la vie, d’avoir échangé autant de tendresse, de sourires, d’avoir joué et rit. Pour tous ces moments hors du temps avec vous qui m’ont permis de prendre du recul, de réaliser que la vie est un magnifique cadeau, et m’ont permis de persévérer : MERCI. A Fanny et Lowik, sans vous la vie aurait beaucoup moins de saveur. Si je réussi cette thèse, c’est en partie grâce à vous. Merci pour les questions et remarques qui m’ont déstabilisé mais qui m’ont permis de me remettre en question et d’avancer. Fanny, merci de comprendre la petite biologiste que je suis et d’avoir partagé tous ces trucs et astuces. Ton soutien a été précieux, tout comme ton sourire et ta joie qui m’ont fait garder le sourire et souvent reprendre des forces. Lowik, tu as le don pour amuser la galerie, semer une bonne ambiance, lancer des phrases cinglantes qui titillent mais permettent de repenser les choses autrement. Merci d’être toi, de rester toujours disponible pour moi et de m’avoir aidé à surmonter ce beau défi, notamment en nous proposant de belles sorties, pique‐nique… pour que je puisse faire des pauses et reprendre des forces. A mes parents, sans qui je ne serais pas là aujourd’hui. Papa et Maman, merci pour votre patience et votre amour. Merci d’être toujours là pour moi tout en me laissant libre. Merci pour vos encouragements, et d’avoir réussi à trouver les mots pour m’aider à surmonter les épreuves et les découragements. Merci de m’avoir forcé à réfléchir, à voir les choses différemment, à sortir de ma zone de confort, à me dépasser et surtout à me poser les bonnes questions au bon moment. Merci d’avoir accepté mes choix, et de m’aider à aller jusqu’au bout. Vous m’avez aidé à murir et vous continuez inlassablement de la faire. Vous avez grandement participé à la réussite de ma thèse (et de beaucoup d’autres belles réussites !). Enfin je dédie ces dernières lignes à Guillaume, mon mari. Merci de m’accompagner tous les jours sur les chemins de la vie. Merci d’avoir accepté de partager ma vie, et de m’avoir encouragé à faire cette thèse. Merci pour ta patience, surtout lorsque je te disais, j’essaye de ne pas rentrer trop tard et que je n’y arrivais pas. Merci de m’avoir demandé en mariage et d’avoir accepté de m’épouser dans une période où je n’étais pas très présente. Tu es resté là discrètement à mes côtés, sans faillir et j’espère pouvoir en faire autant pour toi. Merci pour tes sourires, tes blagues qui ont toujours su dissiper les nuages et me permettre d’entrevoir la vie et cette thèse beaucoup plus positivement. Merci de m’avoir encouragé tout au long de ces 4 années et de m’avoir sans cesse motivé à aller jusqu’au bout. Tu as ta part dans l’accomplissement de cette thèse ! 2 TABLE OF CONTENT Acknowledgements ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 LIST OF FIGURES ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 6 LIST OF TABLES ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 8 ABBREVIATIONS ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 9 INTRODUCTION ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 12 I.
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    UNIVERSIDAD AUTÓNOMA DE MADRID Departamento de Bioquímica Characterization and regulation of Kv1.5-Kvβ1.3 complex. ÁLVARO MACÍAS MARTÍNEZ Madrid 2014 Departamento de Bioquímica Facultad de Medicina UNIVERSIDAD AUTÓNOMA DE MADRID Characterization and regulation of Kv1.5-Kvβ1.3 complex. Memoria presentada para optar al grado de Doctor con Mención Internacional por la Universidad Autónoma de Madrid presenta el Licenciado en Biología: ÁLVARO MACÍAS MARTÍNEZ Bajo la dirección de: Dra. Carmen Valenzuela Miranda Dra. Teresa González Gallego Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM) Madrid, 2014 El trabajo descrito en la presente Tesis Doctoral ha sido llevado a cabo en el Departamento de Modelos Experimentales de Enfermedades Humanas del Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM) y ha sido financiado por los siguientes proyectos de investigación: Mecanismos implicados en la regulación por kinasas del ensamblaje entre Kvα1.5 y Kvβ1.3. CICYT (SAF2007-65868). 2007-2010. Investigador principal: Carmen Valenzuela Miranda. Red Temática de Investigación Cooperativa RECAVA. FIS (RD06/0014/0006). 2007-2010. Investigador principal: Lisardo Boscá Gomar. Modulación adrenérgica de los canales Kv1.5-Kvβ1.3 expresados en diferentes tipos de células cardiovasculares. CICYT (SAF2010- 14916) 2011-2014. Investigador principal: Carmen Valenzuela Miranda. Red de Investigación Cardiovascular. FIS (RD12/0042/0019). 2012-2014. Investigador principal: Carmen Valenzuela Miranda. Además, la realización de esta Tesis Doctoral ha sido posible gracias al disfrute de una beca predoctoral de la Junta de Ampliación de Estudios (JAE-Predoc), del Consejo Superior de Investigaciones Científicas. A mi familia, a ti que lees estas líneas y sobre todo, a mis chicas, Sonia y Emma, mis pilares, mi equilibrio, mi todo.
  • Whole Exome Sequencing Reveals NOTCH1 Mutations in Anaplastic Large Cell Lymphoma and Points to Notch Both As a Key Pathway and a Potential Therapeutic Target

    Whole Exome Sequencing Reveals NOTCH1 Mutations in Anaplastic Large Cell Lymphoma and Points to Notch Both As a Key Pathway and a Potential Therapeutic Target

    Non-Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target Hugo Larose, 1,2 Nina Prokoph, 1,2 Jamie D. Matthews, 1 Michaela Schlederer, 3 Sandra Högler, 4 Ali F. Alsulami, 5 Stephen P. Ducray, 1,2 Edem Nuglozeh, 6 Mohammad Feroze Fazaludeen, 7 Ahmed Elmouna, 6 Monica Ceccon, 2,8 Luca Mologni, 2,8 Carlo Gambacorti-Passerini, 2,8 Gerald Hoefler, 9 Cosimo Lobello, 2,10 Sarka Pospisilova, 2,10,11 Andrea Janikova, 2,11 Wilhelm Woessmann, 2,12 Christine Damm-Welk, 2,12 Martin Zimmermann, 13 Alina Fedorova, 14 Andrea Malone, 15 Owen Smith, 15 Mariusz Wasik, 2,16 Giorgio Inghirami, 17 Laurence Lamant, 18 Tom L. Blundell, 5 Wolfram Klapper, 19 Olaf Merkel, 2,3 G. A. Amos Burke, 20 Shahid Mian, 6 Ibraheem Ashankyty, 21 Lukas Kenner 2,3,22 and Suzanne D. Turner 1,2,10 1Department of Pathology, University of Cambridge, Cambridge, UK; 2European Research Initiative for ALK Related Malignancies (ERIA; www.ERIALCL.net ); 3Department of Pathology, Medical University of Vienna, Vienna, Austria; 4Unit of Laboratory Animal Pathology, Uni - versity of Veterinary Medicine Vienna, Vienna, Austria; 5Department of Biochemistry, University of Cambridge, Tennis Court Road, Cam - bridge, UK; 6Molecular Diagnostics and Personalised Therapeutics Unit, Colleges of Medicine and Applied Medical Sciences, University of Ha’il, Ha’il, Saudi Arabia; 7Neuroinflammation Research Group, Department of Neurobiology, A.I Virtanen Institute
  • Downloaded from the App Store and Nucleobase, Nucleotide and Nucleic Acid Metabolism 7 Google Play

    Downloaded from the App Store and Nucleobase, Nucleotide and Nucleic Acid Metabolism 7 Google Play

    Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 https://doi.org/10.1186/s13023-021-01727-2 REVIEW Open Access Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app Eva M. M. Hoytema van Konijnenburg1†, Saskia B. Wortmann2,3,4†, Marina J. Koelewijn2, Laura A. Tseng1,4, Roderick Houben6, Sylvia Stöckler‑Ipsiroglu5, Carlos R. Ferreira7 and Clara D. M. van Karnebeek1,2,4,8* Abstract Background: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disabil‑ ity (collectively ‘treatable IDs’). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identifcation of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation. Methods: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classifcation of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is avail‑ able. Data on clinical symptoms, diagnostic testing, treatment strategies, efects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features. Results: Our review identifed 116 treatable IDs (139 genes), of which 44 newly identifed, belonging to 17 ICIMD categories.