Study of vesicular glycolysis in health and Huntington’s Disease Maximilian Mc Cluskey To cite this version: Maximilian Mc Cluskey. Study of vesicular glycolysis in health and Huntington’s Disease. Neurons and Cognition [q-bio.NC]. Université Grenoble Alpes [2020-..], 2021. English. NNT : 2021GRALV006. tel-03251320 HAL Id: tel-03251320 https://tel.archives-ouvertes.fr/tel-03251320 Submitted on 7 Jun 2021 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. THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE GRENOBLE ALPES Spécialité : Neurosciences, Neurobiologie Arrêté ministériel : 25 mai 2016 Présentée par Maximilian Mc CLUSKEY Thèse dirigée par Frédéric SAUDOU et co-encadrée par Anne-Sophie NICOT préparée au sein du Grenoble Institut des Neurosciences dans l'École Doctorale de Chimie et Sciences du Vivant Study of vesicular glycolysis in health and Huntington’s disease Thèse soutenue publiquement le 04/02/2021, devant le jury composé de : Mr, Frédéric, DARIOS Chargé de recherche INSERM, Institut du Cerveau, rapporteur Mme, Carine, POURIÉ Professeure des universités, Université de Lorraine, rapporteuse Mr, Hervé, DUBOUCHAUD Professeur des Universités, Université Grenoble Alpes, examinateur Mme, Isabelle, ARNAL Directrice de recherche CNRS, Grenoble Institut des Neurosciences, présidente Mr, Frédéric, SAUDOU Professeur des universités - Practicien hospitalier, Grenoble Institut des Neurosciences, directeur de thèse, Invité Mme, Anne-Sophie, NICOT Maitre de conférence des universités, Grenoble Institut des Neurosciences, co-encadrante, Invité 1 2 ACKNOWLEDGEMENTS I would first like to thank the members of my jury, Dr. Frédéric Darios, Pr. Carine Bossenmeyer-Pourié, Pr. Hervé Dubouchaud and Dr. Isabelle Arnal. Your time spent reading, commenting and discussing this work has been highly appreciated. I would also like to thank my PhD supervisor, Pr. Frédéric Saudou, and co-supervisor, Dr. Anne-Sophie Nicot, for their guidance and trust in my abilities, that has been instrumental in rendering this work possible. I would finally like to thank all members of the team that contributed in some way to this work and made my time at the Grenoble Institute of Neuroscience that much more meaningful. 3 Contents I. ABSTRACT ....................................................................................................................... 8 II. RÉSUMÉ .......................................................................................................................... 10 III. ABBREVIATIONS .......................................................................................................... 12 IV. LIST OF FIGURES .......................................................................................................... 15 V. INTRODUCTION ............................................................................................................ 16 A. Chapter 1: Huntington’s disease .................................................................................. 16 1. General description of Huntington’s disease ........................................................... 16 a) Discovery & history of Huntington’s disease .................................................... 16 b) Prevalence, statistics & heritability of Huntington’s disease in humans ........... 16 c) Symptoms .......................................................................................................... 19 (1) Motor .............................................................................................................. 19 (2) Cognitive ........................................................................................................ 19 (3) Psychiatric ...................................................................................................... 20 (4) Other symptoms ............................................................................................. 21 2. Animal models of Huntington’s disease .................................................................. 22 a) Mouse models .................................................................................................... 22 b) Other models ...................................................................................................... 23 3. Neurodegeneration and cellular dysfunction ........................................................... 24 a) Neurodegeneration ............................................................................................. 24 b) Cellular features and dysfunctions ..................................................................... 26 (1) Inclusion bodies.............................................................................................. 26 (2) Cortico-striatal imbalance .............................................................................. 26 (3) Axonal transport ............................................................................................. 28 (4) Energy metabolism ......................................................................................... 29 (5) Synaptic transmission ..................................................................................... 30 (6) Glia ................................................................................................................. 31 (7) Other dysfunctions ......................................................................................... 33 4. Treating Huntington’s disease ................................................................................. 34 a) Symptomatic treatment ...................................................................................... 34 b) Genetic therapy .................................................................................................. 34 c) Non-genetic therapy ........................................................................................... 36 B. Chapter 2: Huntingtin protein and function ................................................................. 38 1. From huntingtin gene to huntingtin protein ............................................................. 38 a) The huntingtin gene and transcription ............................................................... 38 b) Huntingtin localization....................................................................................... 38 4 c) HTT protein structure ........................................................................................ 39 d) HTT interactors .................................................................................................. 41 e) HTT proteolysis ................................................................................................. 41 2. Huntingtin post-translational modifications ............................................................ 42 a) Acetylation ......................................................................................................... 42 b) SUMOylation and ubiquitination ....................................................................... 43 c) Phosphorylation ................................................................................................. 43 d) Palmitoylation and methylation ......................................................................... 44 3. Huntingtin functions ................................................................................................ 45 a) Axonal transport................................................................................................. 45 b) Endocytosis ........................................................................................................ 46 c) Ciliogenesis ........................................................................................................ 47 d) Cell division ....................................................................................................... 47 e) Protein degradation ............................................................................................ 47 f) Transcription ...................................................................................................... 48 C. Chapter 3: Axonal transport ......................................................................................... 49 1. Basics of axonal transport ........................................................................................ 49 a) General description of axonal transport ............................................................. 49 b) Molecular motors ............................................................................................... 50 c) Axonal cargo dynamics and motors ................................................................... 53 (1) Fast axonal transport ...................................................................................... 53 (2) Slow axonal transport ..................................................................................... 56 2. Regulating and powering axonal transport .............................................................. 57 a) Regulation mechanisms of axonal