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.
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