Iron is essential for numerous biosynthetic and metabolic activities in the brain. In the brain, oligodendrocytes have a relatively high metabolic rate and contain a high percentage of iron requiring enzymes. Consequently, these cells have a high demand for iron. Indeed, oligodendrocytes are the predominant cells to stain for iron in the brain. Consistent with the high iron requirements of oligodendrocytes are the observations that hypomyelination is associated with iron deficiency and peak iron uptake in the neonatal brain coincides with the onset of myelination. A significant unknown in the study of iron, oligodendrocytes and myelination is the means by which oligodendrocytes acquire iron. The majority of cells including neurons in the brain acquire iron delivered by transferrin through its receptor that is expressed on their cell surface. However, mature oligodendrocytes fail to express transferrin receptor based on both immunohistochemical data and autoradiography. The mRNA for transferrin receptors is not detected in white matter with in situ hybridization even during experimental iron deficiency. Therefore, oligodendrocytes must have a non-transferrin dependent system to obtain iron. We have evidence that receptors for ferritin are selectively expressed in white matter tracts in mice and humans and oligodendrocytes in cell culture. Furthermore, the expression of these receptors is altered in the vicinity of plaques in Multiple Sclerosis. The physiological advantage of expressing a receptor for ferritin is that oligodendrocytes do not have to compete with neurons for iron. Thus the working hypothesis for this application is that there is a ferritin binding protein that is selectively expressed by oligodendrocytes and that this is the mechanism by which these cells obtain iron. The goal of this project is to purify the ferritin receptor and clone the gene. This project will significantly alter our thinking on brain iron transport and open novel directions for research in oligodendrocyte biology and diagnositic and therapeutic strategies in demyelinating disorders ? ?
