Iron Metabolism in Oligodendrocytes: The Role of Ferritin and Ceruloplasmin
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Iron deficiency leads to hypomyelination both in humans and animal models, and the neurological sequelae of hypomyelination are significant. Therefore, understanding mechanisms of iron import into oligodendrocytes is necessary for planning effective strategies for iron supplementation. Ferritin is an intracellular iron storage protein that is highly expressed by oligodendrocyte progenitor cells (OPCs). To determine the role of ferritin on OPC maturation and myelination, we used the Cre-lox system to specifically knock-out the heavy subunit of ferritin, (Fth) in OPCs. We performed immunohistochemistry, western blot, and electron microscopy to analyze myelin protein expression and OPC maturation at postnatal days 15 and 30. At both time points, we found a decrease in the expression levels of myelin proteins, a substantial reduction in the percentage of myelinated axons and a decrease in the number of myelinating oligodendrocytes. These results indicate that Fth is important for appropriate OPC maturation and suggest that this protein is essential for the normal myelination of the mouse brain. Remyelination requires the recruitment of OPCs to demyelinated lesions followed by their maturation to myelin-forming oligodendrocytes. Iron is required in many enzymes that influence myelin formation, metabolism, proliferation and differentiation of OPCs, and the deposition of myelin membranes. Therefore, we used the cuprizone model of myelin injury and repair to study how the loss of Fth affects the maturation of OPCs through remyelination. We performed immunohistochemistry, western blot, and electron microscopy experiments to determine if remyelination is affected when Fth is deleted in NG2 positive OPCs. Our data indicate that Fth expression by OPCs is crucial for the normal remyelination of the adult brain. Fth deficient OPCs do not mature normally and remyelinate the adult brain less efficiently than control OPCs. These data suggest that OPCs generated after demyelination need to synthesize new Fth to store iron for a successful remyelination. Ceruloplasmin (Cp) is a ferroxidase that oxidizes toxic ferrous iron (Fe2+) to non-toxic ferric iron (Fe3+) in order to prevent damage to the cell from reactive oxygen species. During the myelination process OPCs express high levels of Cp but the function of this ferroxidase in OPC maturation is completely unknown. Thus, in order to determine the role of Cp in OPC development and myelination we conditionally knocked-out Cp in OPCs using the Cre-lox system. No changes in the levels of myelin protein expression or in the total number of mature myelinating oligodendrocytes were found. However, we detected alterations in the total number and in the percentage of mitotic OPCs. This data suggest that Cp activity is not essential for OPC maturation and myelination during the postnatal development of the mouse brain but probably this enzyme is playing a role in OPC generation and/or proliferation.