Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier

Wu, Lung‐Sheng; Leenders, A.G.M.; Cooperman, Sharon; Meyron-Holtz, Esther G.; Smith, Sophia R.; Land, William; Tsai, Robert Y.L.; Berger, Urs V.; Sheng, Zu Hang; Rouault, Tracey A.

doi:10.1016/j.brainres.2003.10.066

Cited by 184 publications

(163 citation statements)

References 28 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: 90%

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: 90%

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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“…4e, 5a). Wu et al [32] localized ferroportin to synaptic vesicles by immuno-electron microscopy, and their work is of immediate interest to the pathogenesis of grumose degeneration. The authors suggested that the presence of an IRE in the 5Ј-UTR of ferroportin mRNA makes synapses vulnerable to iron toxicity.…”

Section: Ferroportin In the Dentate Nucleusmentioning

confidence: 99%

The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins

et al. 2007

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Frataxin deWciency in Friedreich's ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal controls by biochemical and microscopic techniques. Total iron (1.53 § 0.53 mol/g wet weight) and ferritin (206.9 § 46.6 g/g wet weight) in FRDA did not signiWcantly diVer from normal controls (iron: 1.78 § 0.88 mol/g; ferritin: 210.9 § 9.0 g/g) but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 conWrmed neuronal loss while endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation of mitochondrial iron dysmetabolism in the terminals

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“…Therefore, mitochondria would be expected to have a putative function as an iron transporter to axon terminals. In addition, ferroportin (an iron exporter) is present on synaptic vesicles, suggesting that Fe(II) may be released into the synaptic cleft (Wu et al, 2004).…”

Section: ) Neuronsmentioning

confidence: 99%

“…Ferroportin is localized on the vent ricular side of ependymal cells, suggesting that ferroportin exports iron from the brain parenchyma and circulation into the cerebro-spinal fluid (Wu et al, 2004).…”

Section: ) Specific Cell Typesmentioning

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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Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier

Cited by 184 publications

References 28 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

The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins

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

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