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The Timing of Oligodendrocyte Cell Death Determines the Potential of Myelin Recovery During Brain Postnatal Development

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The Timing of Oligodendrocyte Cell Death Determines the Potential of Myelin Recovery During Brain Postnatal Development The timing of oligodendrocyte cell death determines the potential of myelin recovery during brain postnatal development. Asghar Shabbir To cite this version: Asghar Shabbir. The timing of oligodendrocyte cell death determines the potential of myelin recovery during brain postnatal development.. Biochemistry, Molecular Biology. Université de Strasbourg, 2013. English. NNT : 2013STRAJ089. tel-01410528 HAL Id: tel-01410528 https://tel.archives-ouvertes.fr/tel-01410528 Submitted on 6 Dec 2016 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 414 [Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques INSERM U 1119] THÈSE présentée par : [ Asghar SHABBIR ] soutenue le : 1er Juillet 2013 pour obtenir le grade de : Docteur de l’u niversité de Strasbourg Discipline/ Spécialité : Neurosciences LE PROGRAMME D’INDUC TION DE LA MORT CELLULAIRE DES OLIGODENDROCYTES DETERMINE LE POTENTIEL DE REPA RATION DE LA MYÉLINE AU COURS DU DÉVELOPPEMENT THÈSE dirigée par : M. GHANDOUR Said (Directeur de recherche au CNRS, Université de Strasbourg) RAPPORTEURS : M. SCHUMACHER Michael (Directeur de recherche, INSERM, Université Paris-Sud) M. MASSAAD Charbel (Professeur, Université Paris Descartes) AUTRES MEMBRES DU JURY : Mme. BOEHM Nelly (Professeur, Université de Strasbourg) Examinateur M. MENSAH-NYAGAN Guy (Professeur, Université de Strasbourg) Membre invité I Dedicte this Humble Effort to my Parents and all the Family 2 ACKNOWLEDGMENTS I feel enormous delight to convey my honest gratitude to my supervisor, Dr. Said GHANDOUR, for making it possible for me to work in such a prestigious scientific environment. He has been very supportive, encouraging and kind. I owe a great deal of appreciation for his valuable advice, constructive criticism and extensive discussions around my work. It has been a great honor to work under his supervision. I wish to express my cordial appreciation to the examiners, Dr. Michael SCHUMACHER and Prof. Charbel MASSAAD, Prof. Nelly BOEHM and Prof. Guy MENSAH-NYAGAN for the acceptance of being members of the examination committee. I feel immense pleasure to gratefully acknowledge to Prof. Guy MENSAH-NYAGAN, director of our present INSERM U 1119 laboratory and Dr. Christian KELCHE, director of the former laboratory and to all the members of the two laboratories. I am greatly thankful particularly to Elisabeth TRIFILIEFF, Jérôme DE SEZE, Jérôme STEIBEL , Gabrielle RUDOLF, Laurence MEYER, Christine PATTE-MENSAH, Brigitte SAMAMA, Cristina ANTAL, Nicolas COLLONGUES, Jean-Baptiste CHANSON and Susana BRUN and for their valuable suggestions as members of the laboratory. I extend my admiration and appreciation to Julien GRAFF, Dao LAM and Roland BURY for all their assistance and support. 3 No acknowledgment could ever adequately express my obligation and humble thanks to my Pakistani friends Ghulam HUSSAIN, Rizwan ASLAM, Sultan ALI, Adnan NIAZI, Azhar AYAZ, Rashad HUSSAIN, Nauman ZAHID, Sarfraz SHAFIQ and Muhammad AZEEM who always stood beside me in the hour of need. I am unable to find appropriate words to express my deep gratitude for Higher Education Commission of Pakistan, for providing me this opportunity to work in this reputed scientific community to learn and improve my scientific skills, knowledge and rational thinking. I am perpetually grateful to my beloved parents and all the family members for their unconditional love, loyalty, endurance, countless prayers and endless efforts . They have always been a source of inspiration for me. Asghar SHABBIR 4 Table of Contents Title Page No Aknowlegements 3 List of contents 5 List of figures 11 List of abbreviations 13 Résumé 16 Summary 25 I. Introduction 32 I-1 Central Nervous System (CNS) 33 1.1 Functions of CNS 33 1.1.1 Integration of information 33 1.1.2 Homeostasis 33 1.1.3 Mental Activity 33 1.1.4 Control of muscles and glands 34 1.2 Cells of CNS 34 1.2.1 Neurons 34 1.2.2 Neuroglia 34 1.2.2.1 History and discovery of Neuroglial cells 34 1.2.2.1.1 Pre-Cajalian period 35 1.2.2.1.2 Cajalian period 36 1.2.2.1.3 Post-Cajalian period 37 I-2 Astrocytes 39 2.1 Morphology 39 2.1.1 Fibrous and Protoplasmic astrocytes 39 2.1.2 Radial glia during development 40 2.2 Identification 41 2.3 General Functions of Astrocytes 41 2.3.1 Synapse transmission and neuron survival 41 2.3.2 Synapse stabilization and elimination 41 2.3.3 Blood brain barrier 42 2.3.4 Support 42 2.3.5 Astrocytes and inflammatory response 43 2.3.6 Astrocytes as energy regulators 43 2.4 Astrocytes and myelin 43 5 2.4.1 Role in myelination 44 2.4.2 Inhibition of remyelination 45 2.4.2.1 Formation of glial scar 45 2.4.2.2 Astrocytes prevent OPC migration and maturation 45 2.4.3 Protective effects of astrocytes that promote neuroprotection and 46 myelin repair 2.4.4 Release of extracellular matrix related Factors 46 2.4.5 Astrocyte-Derived Chemokines production 47 I-3 Microglia 49 3.1 Origin of microglia 49 3.2 Morphology 50 3.3 Identification 52 3.4 Activation of microglia 52 3.5 General functions of microglia 53 3.5.1 Regulators of CNS immunity 53 3.5.2 Maintenance of microenvironment 54 3.5.3 Cytotxic effects 54 3.5.4 Microglia and development 54 3.5.5 Neueroprotection 55 3.5.6 Housekeepers 55 3.5.7 Antigen presentation 55 3.5.8 Promotion of repair 55 3.6 Microglia and myelination 56 3.6.1 Interaction with oligodendrocytes 56 3.6.2 Microglial activation 56 3.6.3 T-cells infiltration 56 3.6.4 Microglia as macrophages 58 I-4 Oligodendrocytes 60 4.1 Oligodendrocyte morphology 60 4.2 Classification of oligodendrocytes 61 4.3 Origin and differentiation of Oligodendrocytes 62 4.3.1 Common precursors for neurons and glia: pluripotentiality of stem 64 cells 6 4.3.2 Oligodendrocyte precursors in the ventricular zone 65 4.3.3 Oligodendrocyte progenitors in the SVZ 66 4.4 Oligodendrocyte migration 68 4.5 Oligodendrocyte maturation 70 4.6 Factors necessary for oligodendrocyte maturation and survival 73 4.6.1 Growth Factors 74 4.6.1.1 Platelet derived growth factor (PDGF) 74 4.6.1.2 Basic fibroblast growth factor (bFGF) 74 4.6.1.3 Insulin-like growth factor I 75 4.6.1.4 Neurotrophin-3. (NT-3) 76 4.6.1.5 Glial growth factor (GGF) 76 4.6.1.5 Ciliary neurotrophic factor (CNTF) 76 4.6.1.6 Interleukin-6 and Interleukin 2 (IL-6, IL-2) 76 4.6.1.8 Transforming growth factor (TGF) 76 4.6.1.9 Vascular endothelial growth factor (VEGF-A) 77 4.6.1.10 Hepatocyte growth factor (HGF) 77 4.6.1.11 Fibroblast growth factor receptor 1(FGFR1) 77 4.6.1.12 Pigment epithelium-derived factor (PEDF) 78 4.6.2 Other proteins and receptors 78 4.6.2.1 Poly Sialic Acid Neural Cell Adhesion Molecule (PSA- 78 NCAM) 4.6.2.2 NG2 79 4.6.2.3 Erythropoietin 79 4.6.2.4 Glutamate and their receptors (NMDA) 80 4.6.2.5 Semaphorin 3F 80 4.6.2.6 Semaphorin 6A (Sema6A) 80 4.6.2.7 Sema4D 81 4.6.2.8 Cellular prion protein (PrPc) 81 4.6.2.9 Slit 2 81 4.6.3 Genes and Transcription factors 82 4.6.3.1 Sonic hedgehog 84 4.6.3.2 Transcription factors Olig1 and Olig2 84 4.6.3.2.1 Olig2 Phosphorylation 86 7 4.6.3.3 Sox 9 and 10 87 4.7 Markers of oligodendrocyte lineage 87 4.8 Functions of oligodendrocytes 89 4.10.1 Saltatory conduction 89 4.10.2 Source of CNS iron 90 4.10.3 Maintenance of functional structure 90 4.10.4 Axon survival 91 I-5 Myelin 92 5.1 Nodes of Ranvier 92 5.2 Myelin architecture 92 5.3 Myelin Biochemistry 93 5.3.1 Lipids 95 5.3.2 Proteins 96 5.3.2.1 Proteolipid protein (PLP). 97 5.3.2.2 Myelin basic proteins (MBP) 98 5.3.2.3 2′, 3′ -Cyclic nucleotide 3’ -phosphodiesterase (CNP) 99 5.3.2.4 Myelin-associated glycoprotein (MAG) 100 5.3.2.5 Myelin oligodendrocyte glycoprotein (MOG) 101 5.3.2.6 Oligodendrocyte-myelin glycoprotein (OMgp) 102 5.3.2.7 Paranodal proteins 102 5.3.3 Enzymes associated with myelin 103 5.4 Steps and timing of myelination 105 5.5 Myelin Function 106 5.5.1 Physiology 106 5.5.2 Pathophysiology 107 5.6 Myelin associated disorders 108 5.6.1 Multiple sclerosis (MS) 108 5.6.1.1 Types of MS 108 5.6.1.2 Factors involved in MS 110 5.6.1.3 Clinico-pathological characteristics of MS 111 5.6.2 Leukodystrophies 111 5.6.2.1 Adrenoleukodystrophy (ALD) 112 5.6.2.2 Globoid Cell Leukodystrophy (Krabbe’s Disease) 112 8 5.6.2.3 Metachromatic Leukodystrophy 112 5.6.2.4 Pelizaeus-Merzbacher Disease (PMD) 113 5.6.2.5 Alexander’s Disease 113 5.6.3 Demyelination and axonal injury 114 5.6.3.1 Axonal injury in multiple sclerosis 114 5.6.3.1.1 Early axonal transaction in brain MS lesions 115 5.6.3.1.2 Inflammation mediated axonal degeneration in MS 116 5.6.3.2 Axonal Damage in Leukodystrophies 117 5.6.3.2.1 X-linked adrenoleukodystrophy 117 5.6.3.2.2 Metachromatic leukodystrophy 117 5.6.3.2.3 Krabbe’s disease 117 5.6.3.2.4 Pelizaeus-Merzbacher 117 5.7 Therapeutic strategies to promote remyelination 118 5.7.1 Transplantation of exogenous cells 118 5.7.2 Promoting endogenous remyelination 119 5.7.2.1 Growth factors and related molecules 120 5.7.2.2 Hormones 122 I-6 Animal models of demyelination 124 6.1 Immune mediated mouse models 124 6.1.1 Experimental autoimmune encephalomyelitis (EAE) 124 6.2 Virus-induced demyelinating disease
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