Targeted Ablation of Oligodendrocytes Induces Axonal Pathology Independent of Overt Demyelination
| Autor: | Holly S. Cate, Tobias D. Merson, Jo Anne Stratton, Trevor J. Kilpatrick, Laura Jane Oluich, Sze Woei Ng, Pankaj Sah, François Windels, Yao Lulu Xing |
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| Rok vydání: | 2012 |
| Předmět: |
Genetically modified mouse
Proteolipid protein 1 Central nervous system Action Potentials Cell Count Mice Transgenic Biology Pathogenesis Mice Myelin Evoked Potentials Somatosensory medicine Animals Diphtheria Toxin Myelin Sheath Neurons Diphtheria toxin General Neuroscience Multiple sclerosis Brain Articles medicine.disease Axons Oligodendrocyte Mice Inbred C57BL Disease Models Animal Oligodendroglia medicine.anatomical_structure Spinal Cord nervous system Intercellular Signaling Peptides and Proteins Neuroscience Demyelinating Diseases Heparin-binding EGF-like Growth Factor |
| Zdroj: | Journal of Neuroscience. 32:8317-8330 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1053-12.2012 |
| Popis: | The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted. |
| Databáze: | OpenAIRE |
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