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 non- physiological 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 SNglutathione 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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National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-CDIN-D (01))
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Sieber, Beth-Anne
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Buck Institute for Age Research
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Rajagopalan, Subramanian; Rane, Anand; Chinta, Shankar J et al. (2016) Regulation of ATP13A2 via PHD2-HIF1? Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease. J Neurosci 36:1086-95
Choi, Sung W; Gerencser, Akos A; Lee, Donna W et al. (2011) Intrinsic bioenergetic properties and stress sensitivity of dopaminergic synaptosomes. J Neurosci 31:4524-34
Zhu, Wen; Li, Xuping; Xie, Wenjie et al. (2010) Genetic iron chelation protects against proteasome inhibition-induced dopamine neuron degeneration. Neurobiol Dis 37:307-13
Kaur, Deepinder; Rajagopalan, Subramanian; Andersen, Julie K (2009) Chronic expression of H-ferritin in dopaminergic midbrain neurons results in an age-related expansion of the labile iron pool and subsequent neurodegeneration: implications for Parkinson's disease. Brain Res 1297:17-22
Kaur, Deepinder; Lee, Donna; Ragapolan, Subramanian et al. (2009) Glutathione depletion in immortalized midbrain-derived dopaminergic neurons results in increases in the labile iron pool: implications for Parkinson's disease. Free Radic Biol Med 46:593-8
Lee, Donna W; Rajagopalan, Subramanian; Siddiq, Ambreena et al. (2009) Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J Biol Chem 284:29065-76
Lee, Donna W; Kaur, Deepinder; Chinta, Shankar J et al. (2009) A disruption in iron-sulfur center biogenesis via inhibition of mitochondrial dithiol glutaredoxin 2 may contribute to mitochondrial and cellular iron dysregulation in mammalian glutathione-depleted dopaminergic cells: implications for Parkinson's disease Antioxid Redox Signal 11:2083-94
Kaur, Deepinder; Peng, Jun; Chinta, Shankar J et al. (2007) Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging 28:907-13
Kaur, Deepinder; Rajagopalan, Subramanian; Chinta, Shankar et al. (2007) Chronic ferritin expression within murine dopaminergic midbrain neurons results in a progressive age-related neurodegeneration. Brain Res 1140:188-94
Lee, Donna W; Andersen, Julie K; Kaur, Deepinder (2006) Iron dysregulation and neurodegeneration: the molecular connection. Mol Interv 6:89-97

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