Brain Iron Metabolism

Rouault, Tracey A.; Cooperman, Sharon

doi:10.1016/j.spen.2006.08.002

Cited by 251 publications

(219 citation statements)

References 80 publications

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“…4, A and B). Iron efflux by ferroportin also contributes to the homeostatic regulation of intracellular iron levels (55)(56)(57). Similar to recent findings (58), MPTP was found to reduce expression of ferroportin within the SN (Fig.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target ␣ subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1␣ within these neurons. Elevations in mRNA and protein levels of HIF-dependent genes heme oxygenase-1 (Ho-1) and manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of MPTP. MPTP-induced reductions in ferroportin and elevations in nigral and striatal iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in pyruvate dehydrogenase mRNA and activity resulting from MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3% oxygen treated with either PHD inhibitors or an iron chelator. Concordant with our in vivo data, the MPP ؉ -elicited increase in total iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against MPTP neurotoxicity may be mediated by alterations in iron homeostasis and defense against oxidative stress and mitochondrial dysfunction brought about by cellular HIF-1␣ induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with metal-induced oxidative stress.Parkinson disease (PD) 2 is a neurodegenerative disorder primarily associated with loss of dopaminergic (DAergic) neurons of the pars compacta region of the substantia nigra (SNpc). Dopaminergic neurons are particularly prone to oxidative damage due to high levels of inherent reactive oxygen species that are produced during dopamine synthesis or its breakdown by monoamine oxidases or autoxidation to quinones (1-3). Importantly, iron bound to neuromelanin within DAergic neurons can subsequently react with metabolically liberated hydrogen peroxide through the Fenton reaction to produce extremely toxic hydroxyl radicals. If not properly buffered, hydroxyl radicals can stimulate protein oxidation and lipid peroxidation, which is thought to contribute to macromolecular injury and neuronal death. Iron is the most abundant metal in the brain and some degree of accessible reactive iron is necessary for brain viability as it serves as a cofactor in DNA, RNA, and protein synthesis and for heme and non-heme enzymes involved in both mitochondrial respiration and neurotransmitter synthesis (4). Although iron deficiencies early in life ...

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Section: Discussionsupporting

confidence: 89%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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“…It appears that neurons with a large cell body or a long axon continually require iron to maintain their high metabolic activities and therefore contain a relatively large amount of iron in the cytosol that is histochemically detectable. Rouault and Cooperman (2006) reported that ferritin is present in the axons of normal neurons in the brain, implying that there may be a trafficking mechanism that permits ferritin to carry iron from the neuronal cell body to the synapse. Rouault (2001) also suggested that ferritin could be degenerated within lysosomes and that Fe(II) is released in distal axons although we rarely observed iron-positive lysosomes in axons.…”

Section: ) Neuronsmentioning

confidence: 99%

Cellular and subcellular localizations of nonheme ferric and ferrous iron in the rat brain: a light and electron microscopic study by the perfusion-Perls and -Turnbull methods

Meguro

Asano

Odagiri

et al. 2008

Archives of Histology and Cytology

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“…IREs in the 3' UTR, such as in transferrin receptor, increase protein levels by increasing mRNA stability [61]. Examples of proteins regulated by IREs include transferrin receptor, mitochondrial aconitase, the erythroid isoform of 5-aminolevulainate synthase, ferroportin, the H-and Lsubunits of ferritin, and A PP [62].…”

Section: Alpha-synuclein Gene Expressionmentioning

confidence: 99%

“…Ferritin translation can take place after eIF4E promotes eIF4G binding to eIF3 and hence 40S ribosome recruitment. The 40S ribosome then scans ferritin mRNAs before eIF2-a dependent 60S ribosome subunit "joining step" when protein synthesis begins [62].…”

Section: Alpha-synuclein Gene Expressionmentioning

confidence: 99%

Oxidative Stress in Parkinson`s Disease

Friedlich

Smith²,

Zhu³

et al. 2009

TOPATJ

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Abstract:Parkinson's disease (PD) is a progressive, age-related movement disorder, whose neuropathology is characterized by degeneration of the afferent pigmented neurons of the substantia nigra. Also associated with PD neuropathology are disrupted iron homeostasis, oxidative stress, and intracellular deposition of alpha-synuclein protein in Lewy bodies. Here we review oxidative stress mechanisms in Parkinson's disease, with emphasis on the relationship between oxidative stress and alpha-synuclein gene expression.

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Brain Iron Metabolism

Cited by 251 publications

References 80 publications

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Cellular and subcellular localizations of nonheme ferric and ferrous iron in the rat brain: a light and electron microscopic study by the perfusion-Perls and -Turnbull methods

Oxidative Stress in Parkinson`s Disease

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