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The trace elements iron (Fe), copper (Cu) and zinc (Zn) play important roles in neuronal differentiation, function, and survival. These metals have been implicated in neuropsychiatric and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and Wilson's diseases, that have been associa ted with changes in neuronal proliferation and differentiation, and are characterized by apoptotic neuronal death. The work described in this dissertation explores the molecular roles of Fe, Cu, and Zn, with a particular focus on gene expression during neuronal differentiation and apoptosis. The first part of this work uses both in vivo and in vitro models to explore the role of Fe in neuronal differentiation. This work showed that retinoic acid, a known molecular regulator of neuronal differentiation, may act through its ability to increase expression of ferritin H, a protein that plays a role in neuronal Fe utilization. The second part of this work examined the role of Cu in the molecular mechanisms responsible for neuronal apoptosis. This work showed that Cu toxicity, such as that seen in several neurodegenerative disorders, induces neuronal apoptosis that is dependent on the expression and nuclear translocation of the tumor suppressor protein p53. Because p53 acts as a DNA-binding transcription factor, fo llow-up work used oligonucleotide array to identify p53-target genes that regulate neuronal survival and apoptosis. Both pro-apoptotic genes (IGFBP-6 and c-jun) and anti-apoptotic genes (Hsp 70 and 27) were regulated by p53 under conditions of neuronal Cu-overload. We also showed that p53 trafficking was regulated by Zn. High concentrations of neuronal Zn prevented nuclear translocation of p53, inhibiting it functions in gene transcription and apoptosis. The final part of this work used subtracted cDNA libraries, differential hybridization, and high throughput gene expression profiling (microarray) to identify new molecular roles of Zn in the olfactory bulb, a region of the brain known to have high concentrations of Zn and an association with several neurological disorders. This work showed that Zn regulates a variety of bulb genes involved in both neuroplasticity and apoptosis, and suggests that previously reported positive effects of caloric restriction on neuronal survival and plasticity are abrogated by the development of Zn deficiency. In summary, this work has identified a number of novel molecular roles for the trace elements Fe, Cu, and Zn in neuronal differentiation and apoptosis, and suggests a role for these metals in neurological disorders associated with changes in neuronal survival.
A Dissertation submitted to the in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Cathy W. Levenson, Professor Directing Dissertation; Charles Ouimet, Outside Committee Member; Marc Freeman, Committee Member; J. Michael Overton, Committee Member; Paul Trombley, Committee Member.
Florida State University
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