title: Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model.
abstract: Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS). Where and how oligodendrocyte damage is initiated in MS is not completely understood. Here, we use a combination of light and electron microscopy techniques to provide a dynamic and highly resolved view of oligodendrocyte damage in neuroinflammatory lesions. We show that both in MS and in its animal model structural damage is initiated at the myelin sheaths and only later spreads to the oligodendrocyte cell body. Early myelin damage itself is characterized by the formation of local myelin out-foldings-'myelinosomes'-, which are surrounded by phagocyte processes and promoted in their formation by anti-myelin antibodies and complement. The presence of myelinosomes in actively demyelinating MS lesions suggests that oligodendrocyte damage follows a similar pattern in the human disease, where targeting demyelination by therapeutic interventions remains a major open challenge.
authors.affiliation: Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Romanelli
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.|Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland.
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mezydlo
authors.affiliation: Max-Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.|Department of Neurology, Georg-August University Göttingen, 37075 Göttingen, Germany.
authors.forename: Marie-Theres
authors.initials: MT
authors.lastname: Weil
authors.affiliation: Department of Neurology, Georg-August University Göttingen, 37075 Göttingen, Germany.|Institute of Neuropathology, Georg-August University Göttingen, 37075 Göttingen, Germany.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
authors.affiliation: Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Nikić
authors.affiliation: Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Potz
authors.affiliation: Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
authors.affiliation: Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Florian E H
authors.initials: FE
authors.lastname: Matznick
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Kreutzfeldt
authors.affiliation: Max von Pettenkofer-Institute and Gene Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.affiliation: Max von Pettenkofer-Institute and Gene Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Karl-Klaus
authors.initials: KK
authors.lastname: Conzelmann
authors.affiliation: Institute of Neuropathology, Georg-August University Göttingen, 37075 Göttingen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.affiliation: Institute of Neuropathology, Georg-August University Göttingen, 37075 Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Department of Physiology and Health Science, Ball State University, Muncie, Indiana 47306, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Routh
authors.affiliation: Max-Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.|Department of Neurology, Georg-August University Göttingen, 37075 Göttingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.|Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany.
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
authors.affiliation: Department of Cellular and Integrative Physiology and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Derron
authors.initials: D
authors.lastname: Bishop
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.|Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany.|Center of Integrated Protein Sciences (CIPS), 81377 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Misgeld
authors.affiliation: Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 81377 Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kerschensteiner
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D003711:Demyelinating Diseases / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D006801:Humans; D021621:Imaging, Three-Dimensional; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000473:pathology*; D009186:Myelin Sheath / Q000473:pathology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000473:pathology* / Q000648:ultrastructure; D009895:Opsonin Proteins / Q000378:metabolism; D015388:Organelles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000906:Antibodies; D009895:Opsonin Proteins; D003165:Complement System Proteins