We previously demonstrated that iron-mediated oxidative stress is causally involved in Parkinson's-related neurodegeneration in a well-established model of the disease, systemic MPTP administration. Iron's elevation in the Parkinsonian substantia nigra (SN) has been postulated to contribute to the selective dopaminergic neurodegeneration in this brain region associated with the disorder. The potential cause(s) of iron dysregulation in the diseased SN, however, is unknown. Iron levels are normally controlled by the physiological action of iron regulatory proteins (IRPs) which bind to iron-regulatory elements (IREs) in the RNAs of ferritin and the transferrin receptor (TfR) regulating their levels and thereby iron homeostasis. IRP1 binding is reported to be aberrantly sustained in the Parkinsonian SN in the face of elevated iron levels, a condition which would normally lead to its decrease. We have recently generated preliminary data suggesting that both increased neonatal dietary iron intake and decreases in SN levels of the thiol antioxidant glutathione result in aberrantly sustained IRP binding in the face of elevated iron levels. Previous studies have demonstrated that exposure of IRP1 to reactive oxygen species results in persistent nonphysiological binding of the protein to IRE sequences. We hypothesize that: (1) increased iron and oxidative stress in the older SN as a consequence of increased neonatal dietary iron intake can result in sustained IRP1 binding and dysregulation of cellular iron homeostasis and (2) sustained depletion in dopaminergic SN glutathione levels can also result in persistent IRP1 binding and iron dysregulation. We propose to test these hypotheses in vivo by assessing the impact of: (1) neonatal iron feeding in a novel transgenic mouse line recently constructed in our laboratory in which levels of glutathione are increased in dopaminergic neurons of the SN and (2) glutathione depletion in a second recently constructed transgenic line in our laboratory in which dopaminergic SN glutathione levels are reduced. We plan to examine oxidative stress and iron homeostasis under both of these experimental conditions in comparison to the genesis of neurodegeneration. The long-terms goal of our studies will be to understand by what mechanism(s) iron dysregulation is occurring in the Parkinsonian SN which contributes to subsequent neurodegeneration associated with the disease. Through a better understanding of the possible intrinsic and extrinsic mechanisms by which iron dysregulation occurs in the Parkinsonian SN, our findings may aid in the development of novel therapies for the disease.
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