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      Myelin damage and repair in pathologic CNS: challenges and prospects

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          Abstract

          Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for CNS repair.

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          Most cited references279

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          Macrophage activation and polarization

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            Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration.

            Mitochondria have a number of essential roles in neuronal function. Their complex mobility patterns within neurons are characterized by frequent changes in direction. Mobile mitochondria can become stationary or pause in regions that have a high metabolic demand and can move again rapidly in response to physiological changes. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders. Research into the mechanisms that regulate mitochondrial transport is thus an important emerging frontier.
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              Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination.

              Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.
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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/255959
                URI : http://loop.frontiersin.org/people/255966
                URI : http://loop.frontiersin.org/people/196211
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                27 July 2015
                2015
                : 8
                : 35
                Affiliations
                [1]Regenerative Medicine Program, Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg MB, Canada
                Author notes

                Edited by: Wilfredo Mellado, Burke-Cornell Medical Research Institute, USA

                Reviewed by: Woong Sun, Korea University College of Medicine, South Korea; Michael Kawaja, Queen’s University, Canada

                *Correspondence: Soheila Karimi-Abdolrezaee, Regenerative Medicine Program, Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Faculty of Health Sciences, College of Medicine, University of Manitoba, 629-Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada, soheila.karimi@ 123456umanitoba.ca
                Article
                10.3389/fnmol.2015.00035
                4515562
                26283909
                9a3738fd-1b17-4c57-9ac7-686f738a8c07
                Copyright © 2015 Alizadeh, Dyck and Karimi-Abdolrezaee.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 May 2015
                : 06 July 2015
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 341, Pages: 27, Words: 0
                Funding
                Funded by: Canadian Institute of Health Research
                Funded by: Craig H. Neilson Foundation
                Funded by: Research Manitoba
                Categories
                Neuroscience
                Review

                Neurosciences
                demyelination,spinal cord injury,cell therapy,oligodendrocytes,remyelination,neural stem cells,oligodendrocyte precursor cells,astrocytes

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