Iron Acquisition Mechanisms in Oligodendrocytes

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According to The World Health Organization, iron deficiency is the foremost nutritional disorder in the world. Iron is essential for normal neurological function and iron deficiency results in cognitive and motor impairments that can last throughout life, and are often irreversible. Many of the neurological problems associated with iron deficiency can be traced to hypomyelination. The role of iron in myelination was established over the past 20 years, by data from the PI's laboratory revealing that oligodendrocytes stain more prominently than any other cell type in the brain for iron. These data were consistent with the relatively high concentration of iron-requiring enzymes involved in myelination. However, a significant omission in the paradigm regarding iron and oligodendrocyte function, how oligodendrocytes acquire iron, has not been identified. We and others reported that despite the relatively high levels of iron in white matter tracts, there was no detectable transferring receptor (the traditional cellular mechanism for iron acquisition) in white matter. Even when iron deficiency is so severe as to cause hypomyelination, transferring receptor expression in white matter is not detectable. We propose the overall hypothesis that H-ferritin is the iron delivery vehicle for oligodendrocytes instead of transferrin. Recently, a member of the semaphorin family, T-cell immunoglobulin mucin domain 2 (Tim-2) was discovered to bind H-ferritin. Thus, the conceptual framework for this line of research is that Tim-2 is the ferritin binding protein that is selectively expressed by oligodendrocytes and is the mechanism by which these cells obtain the iron that is required to produce and sustain myelin. The significance of the proposed research is that we have found a novel, developmentally regulated, selectively expressed, receptor for iron acquisition on oligodendrocytes. Because the only other known ligand for Tim-2 is Sema4A, a protein expressed on antigen presenting cells and activated Band T lymphocytes, a potentially significant future direction that can be pursued following the studies proposed herein will be to explore the possibility of a connection between the immune system and oligodendrocytes via Tim-2 expression on oligodendrocytes that could affect demyelinating disorders. The project is innovative because the aims are designed to establish the following new data on the role of iron in myelination of eNS: i) H-ferritin is the definitive mechanism by which oligodendrocytes acquire iron; ii) the H-ferritin binding protein on oligodendrocytes is Tim-2, iii) that H-ferritin protein can be used as a delivery vehicle to improve myelination following iron deficiency. The knowledge of how iron is managed and delivered to oligodendrocytes as well as the timing of expression of iron acquisition proteins can be expected to inform intervention strategies for the treatment of developmental hypomyelination resulting from iron deficiency and demyelinating disorders and remyelination attempts in the adult such as Multiple Sclerosis.