Regulation of Expression of Iron Binding Proteins in the Nervous System

The projects in my laboratory are designed to understand the cellular and molecular mechanisms by which cells regulate their iron status. Iron is essential for normal function but at the same time too much iron can be toxic. Therefore cells have an exquisite system for regulating iron levels. When these regulatory mechanims become dysfunctional either through damage, disease or genetic modification cell behavior is abnormal and they sometimes die. Iron imbalance is associated with a prooxidative stress and a proinflammatory environment. Much of our work has focused on mechanisms responsible for regulating iron in the brain. One basic function in which iron is required in the brain is for the production of myelin. We have shown that too little iron during perinatal development will result in hypomyelination. We have also provided evidence that iron can contribute to Multiple Sclerosis (MS). We have established that there is too much iron in the brain in a number of neurological disorders including Alzheimer's (AD) and Parkinson's Diseases (PD). In contrast, there appears to be too little iron in the brain in a disorder known as Restless Legs Syndrome. What is clear from our studies is that optimal brain function requires a tightly regulated iron supply and that the iron must be delivered in a timely manner. To determine the mechanism(s) for brain iron delivery and the regulation of those mechanisms we have focused on a number of mouse and rat mutants as a model of human diseases in which the ability to acquire, moblize or store iron has been disrupted. In the context of these studies we have generated a very promising mouse line in which the gene for the iron storage protein, ferritin, has been deleted. This model is helping to understand the contribution of loss of brain iron homeostatic mechanisms to those changes seen in the brain with AD, PD and MS. In the course of these studies on ferritin, we found that in addition to the cytoplasmic location, ferritin can be found in cell nuclei under some conditions. This observation has led us to basic molecular studies on DNA binding and protection as well as intracellular trafficking of ferritin. The evidence strongly indicates that nuclear ferritin is associated with tumorigenesis. Another avenue under exploration in the context of homeostatic mechanisms is the analysis of gene mutations that lead to disruption of iron status. We have identified mutations in the Hfe gene as a risk factor for Alzheimer's Disease and Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease). The Hfe protein is thought to limit iron uptake by cells and a mutation in this protein may promote inflammation and oxidative stress. We also have a line of research aimed at understanding mechanisms of iron uptake into the brain. This line of research should provide insight into how too much iron can enter the brain in disease states. These studies have led to one particularly novel and important finding of a new receptor in the brain for ferritin. This receptor is expressed only by oligodendrocytes in the brain. We are investigating the possibility that the selective expression of ferritin receptors on oligodendrocytes may have medically important implications for Multiple Sclerosis.

In regard to function of iron in the brain, one area of focus is the regulation of those proteins responsible for iron management in cells. The iron management proteins are regulated by cytoplasmic mRNA binding proteins that are known are iron regulatory proteins. Our project is to determine how the cytoplasmic mRNA binding proteins find their target mRNAs. The outcome of these studies may help us understand how a cell can become iron overloaded but also will contribute significantly to our general knowledge of post-transcriptional gene regulation. One additional approach which is aimed at understanding the function of iron in cells is gene expression profiling. In these studies we have asked the question: "what does it mean to a cell at the molecular level to be iron loaded or iron starved". So far, we have identified a dozen novel genes and a number of genes not previously known to be iron responsive. These data are relevant to cancer and Alzheimer's Disease and Restless Legs Syndrome.

Finally, to examine the consequences of iron mismanagement in the brain, we utilize both cell culture and animal models. The cell culture model seeks to identify the intracellular events associated with iron induced stress and uses state of the art microscopic and flurimetric techniques. Sara Robb received the Marian Kies Award from the American Society of Neurochemistry for outstanding graduate research for developing this model in my laboratory.