Iron is essential for oxidative metabolism. The brain, which has a higher rate of oxidative activity than any other organ, has a high iron requirement. Although the brain requires a ready access to iron, it resides behind a barrier which limits its access to plasma iron. Presumably to compensate for the limited access to iron, there are iron rich areas in the brain and an iron rich population of cells (oligodendrocytes). The accumulation of iron must be stringently managed, however, as iron is a potent inducer of free radicals and hence oxidative damage. Oxidative damage and iron dysregulation have been proposed as part of the pathogenesis in a number of common neurological disorders including Alzheimer's and Parkinson's disease and Multiple Sclerosis. The focus of this research program is to understand the mechanism(s) of iron management in the brain with the ultimate goals of elucidating the effect of iron management and mismanagement on neurological function. In this proposal the investigators specifically focus on two proteins of the iron management system: transferrin and ferritin.
In aim 1, they propose to determine the role of transferrin in oligodendrocyte physiology and the role of oligodendrocytes in iron regulation in the brain using a naturally occurring mouse mutant which does not make transferrin.
In aim 2, because ferritin consists of differing ratios of functionally distinct subunits they will determine the cellular distribution of ferritin subunits in the developing brain to elucidate iron utilization among different cell types. In the white matter, ferritin is expressed in select oligodendrocytes and they will use retroviral labeling to determine whether the expression of ferritin in those cells is genetically or epigenetically regulated. Their preliminary developmental analysis also revealed that the H subunit of ferritin (the one capable or rapid detoxification of iron) is localized in neuronal nuclei. Thus in aim 3, they will determine whether ferritin is present in the nucleus to protect nuclear contents from iron induced oxidative damage or if it acts in a sequence specific manner.
In aim 4 we pursue the novel observation of a ferritin receptor in brain which may be found predominantly on oligodendrocytes. Finally, as it is becoming clear the H-ferritin may have a major role in the normal development of the nervous system and a continual role as a cytoprotectant we propose in aim 5 to study the in vivo function of H-ferritin in a mutant mouse in which the H-ferritin gene has been deleted. The brain clearly has an elegant system for iron management. Our research program seeks to continue to define the components of this system. The fine line between iron availability for normal neurological function versus iron availability for induction of oxidative damage can only be understood by elucidation of the mechanisms by which iron is regulated.
