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In acute multiple sclerosis (MS) lesions, axonal pathology and the number of transected axons correlate with the number of immune cells and therefore with inflammatory activity. In addition to the commonly described white matter locations, demyelination also occurs in the gray matter of MS patients. The concept of MS as an inflammatory demyelinating and neurodegenerative disease provides a framework to help explain disease progression and development of permanent neurological disability in MS patients. Prevention of persistent neurological disability is the main goal when treating neurological diseases. In contrast to most neurodegenerative diseases, patients with MS can be identified early before the occurrence of extensive neurodegeneration by the presentation of symptoms mediated by inflammatory demyelination. Therefore, neuroprotective therapeutics may have a greater probability of clinical efficacy in MS patients since treatment can be initiated before extensive axonal loss. Regardless of the cause of MS, axons and neurons are important therapeutic targets.
Oligodendrocytes are remarkable cells. In vertebrate evolution, the advent of oligodendrocytes and myelination transformed the CNS by allowing fast and energy efficient communication between neurons, ultimately fostering the evolution of animals with complex, highly integrated motor, sensory and cognitive functions. In humans, myelination underlies most of the early developmental neurological milestones, and new myelination continues to be important into the third and fourth decades. Human diseases involving oligodendrocyte dysfunction are devastating, and those such as multiple sclerosis (MS) account for a significant proportion of neurological disease. Since the first studies of myelin protein biochemistry in the late nineteenth century, myelin proteins and lipids have received intense experimental investigation. Extensive reviews of the biochemistry, genetics, immunogenicity and localizations of the major myelin proteins and lipids have been published. Recent genomic and proteomic studies have begun to provide a complete list of myelin and oligodendrocyte-enriched molecules. The goal of this chapter is to consider the contributions of different myelin proteins and lipids to (1) the structure of central nervous system (CNS) myelin, (2) the cell biology of myelin formation and (3) their roles in vital interactions between oligodendrocyte and axons. The emerging picture of oligodendrocyte myelination is a process that is extremely fault tolerant and inextricably intertwined with axonal function.
OLIGODENDROCYTES HAVE A HIGHLY POLARIZED SHAPE
Few cells have as extreme a shape as myelinating oligodendrocytes. Before discussing their molecular organization, it is therefore important to have a clear picture of oligodendrocytes and their myelin membranes.
Neurons in the central nervous system (CNS) are extensively interconnected, and consequently almost half of the human brain is occupied by wiring in the form of the myelinated axons. Dysfunction and degeneration of these axons can result in profound and permanent disability. Axons are much more complex than simple wires, however. Signal propagation relies on elaborate ultrastructural specializations at the nodes of Ranvier, which are demarcated by gaps between myelin sheaths. As living extensions of neurons, axons also require constant replenishment of metabolites and organelles such as energy-generating mitochondria. Studies of pathogenesis of myelinated axons are often constrained by microscopic complexity that requires nanometer-scale resolution over substantial three-dimensional distances.
Cells that express the NG2 chondroitin sulfate proteoglycan and platelet-derived growth factor receptor alpha (NG2 glia) are widespread in the adult human cerebral cortex and white matter and represent 10–15% of non-neuronal cells. The morphology and distribution of NG2 glia are similar to, but distinct from, both microglia and astrocytes. They are present as early as 17 weeks gestation and persist throughout life. NG2 glia can be detected in a variety of human central nervous system (CNS) diseases, of which multiple sclerosis is the best studied. NG2 glia show morphological changes in the presence of pathology and can show expression of the Ki-67 proliferation antigen. The antigenic profile and morphology of NG2 glia in human tissues are consistent with an oligodendrocyte progenitor function that has been well established in rodent models. Most antibodies to NG2 do not stain formalin-fixed paraffin-embedded tissues. Advances in our understanding of NG2 glia in human tissues will require the development of more robust markers for their detection in routinely processed human specimens.
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