Distribution of <sup>125</sup>I‐Ferrotransferrin Binding Sites in the Mesencephalon of Control Subjects and Patients with Parkinson's Disease

Faucheux, Baptiste; Hirsch, Étienne C.; Villares, Joào; Selimi, Fekrije; Mouatt‐Prigent, Annick; Javoy‐Agid, F.; Hauw, Jean‐Jacques; Agid, Yves

doi:10.1111/j.1471-4159.1993.tb03527.x

Cited by 54 publications

(37 citation statements)

References 22 publications

(15 reference statements)

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“…In the latter, increased expression of tissue ferritin, the major intracellular sequester of ferric iron, parallels the distribution of the excess iron and largely implicates nonneuronal (glial) cellular compartments (Youdim, 1994). In marked contrast to the ferritin data, the density of transferrin binding sites remains unchanged or varies inversely with augmented iron stores in the substantia nigra and striatum of PD subjects (Mash et al, 1991;Kalaria et al, 1992;Faucheux et al, 1993;Gelman, 1995). These and analogous findings in normal aging and Alzheimer's disease brain specimens (Dwork et al, 1988;Connor et al, 1992;Kalaria et al, 1992;Faucheux et al, 1993; 1993) have led to the important conclusion that, in contradistinction to the situation in most peripheral tissues, transferrin and its receptor play a limited role, if any, in the sequestration of iron by aging and degenerating CNS tissues (Faucheux et al, 1993).…”

Section: Discussioncontrasting

confidence: 66%

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Schipper

Bernier

Mehindate

et al. 1999

Journal of Neurochemistry

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Abstract:Little is currently known concerning the mechanisms responsible for the excessive deposition of redox-active iron in the substantia nigra of subjects with Parkinson's disease (PD). In the present study, we demonstrate that dopamine promotes the selective sequestration of non-transferrin-derived iron by the mitochondrial compartment of cultured rat astroglia and that the mechanism underlying this novel dopamine effect is oxidative in nature. We also provide evidence that up-regulation of the stress protein heme oxygenase-1 (HO-1) is both necessary and sufficient for mitochondrial iron trapping in dopamine-challenged astroglia. Finally, we show that opening of the mitochondrial transition pore (MTP) mediates the influx of non-transferrin-derived iron into mitochondria of dopamine-stimulated and HO-1 -transfected astroglia. Our findings provide an explanation for the pathological iron sequestration, mitochondrial insufficiency, and amplification of oxidative injury reported in the brains of PD subjects. Pharmacological blockade of transition metal trapping by "stressed" astroglial mitochondria (e.g., using HO-1 inhibitors or modulators of the MTP) may afford effective neuroprotection in patients with PD and other neurological afflictions.

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Section: Discussioncontrasting

confidence: 66%

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Schipper

Bernier

Mehindate

et al. 1999

Journal of Neurochemistry

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“…Prior to 59 Fe labeling, bLf was fully desaturated in formiate buffer (0.2 M formic acid-sodium formiate; containing 0.5 M NaH 2 PO 4 and 25 mM EDTA) at pH 3.8 to give apobLf. 59 Fe (18 nmol) (3-25 mCi/mg Fe, Amersham Pharmacia Biotech) was mixed with a solution containing 0.4 mM nitriloacetic acid and 0.05 M NaOH for 5 min at room temperature, and then the pH was adjusted to 8.2 with NaOH.…”

Section: Methodsmentioning

confidence: 99%

“…59 Fe (18 nmol) (3-25 mCi/mg Fe, Amersham Pharmacia Biotech) was mixed with a solution containing 0.4 mM nitriloacetic acid and 0.05 M NaOH for 5 min at room temperature, and then the pH was adjusted to 8.2 with NaOH. ApobLf (37 nmol) dissolved in 0.1 M Tris-bicarbonate buffer (pH 7.6) was added to the iron solution and then incubated for 45 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Receptor-mediated Transcytosis of Lactoferrin through the Blood-Brain Barrier

Fillebeen¹,

Descamps²,

Dehouck³

et al. 1999

Journal of Biological Chemistry

346

243

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Lactoferrin (Lf) is an iron-binding protein involved in host defense against infection and severe inflammation; it accumulates in the brain during neurodegenerative disorders. Before determining Lf function in brain tissue, we investigated its origin and demonstrate here that it crosses the blood-brain barrier. An in vitro model of the blood-brain barrier was used to examine the mechanism of Lf transport to the brain. We report that differentiated bovine brain capillary endothelial cells exhibited specific high (K d ‫؍‬ 37.5 nM; n ‫؍‬ 90,000/cell) and low (K d ‫؍‬ 2 M; n ‫؍‬ 900,000 sites/cell) affinity binding sites. Only the latter were present on nondifferentiated cells. The surface-bound Lf was internalized only by the differentiated cell population leading to the conclusion that Lf receptors were acquired during cell differentiation. A specific unidirectional transport then occurred via a receptor-mediated process with no apparent intraendothelial degradation. We further report that iron may cross the bovine brain capillary endothelial cells as a complex with Lf. Finally, we show that the low density lipoprotein receptor-related protein might be involved in this process because its specific antagonist, the receptor-associated protein, inhibits 70% of Lf transport. Lactoferrin (Lf)1 (1) is a mammalian cationic iron-binding glycoprotein belonging to the transferrin (Tf) family. Despite some striking differences, mainly in the glycan moiety, there are marked sequence and conformational homologies among Lfs from different species, as well as similar general functions (for review, see Ref.2). Many physiological roles have been ascribed to Lf, particularly in the host defense against infection and severe inflammation (for review, see Ref. 3). This broad spectrum of biological functions relies on the interaction of Lf with numerous cells. The binding of Lf to cells is independent of its degree of iron saturation and is mediated mainly via interaction of the cluster of basic amino acids at its NH 2 terminus with sulfated molecules (4, 5). However, Lf is also targeted to specific cell receptors, and only a few of these involved in its uptake have been clearly identified. The 105-kDa Lf receptor characterized on activated human T-cells (6) is expressed at the cell surface of platelets (7), megacaryocytes (8), dopaminergic neurons, and mesencephalon microvessels (9). Lf receptor internalizes Lf, which is subsequently degraded (30 -40%), whereas the remaining fraction is recycled (10). In addition, the low density lipoprotein receptor-related protein (LRP) displays a high affinity for Lf and is responsible for its clearance (11)(12)(13)(14). This is inhibited by RAP, the receptor-associated protein known to be an antagonist for LRP (15). Transcytosis of Lf was described for HT29 cells (16) and was a minor pathway, up-regulated during iron deprivation (17).Lf is produced by exocrine glands (1, 18) and is widely distributed in the body fluids. It is stored in specific granules of neutrophilic leukocytes (19) and is relea...

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“…However, two regional analyses of radiolabeled ferrotransferrin binding sites in the mesencephalon have shown that their density was extremely low in the SNpc of controls and was either unchanged or decreased in PD patients (13,14), which indicates that the increase in nigral iron content reported in surviving neurons (4,8,11) and in glial cells (7) may occur (i) by metabolic changes with a higher penetration of iron without any increased density of transferrin receptors on the soma of DA cells, (ii) by receptors located on other parts of DA neurons (i.e., terminals), and/or (iii) by other pathways. A localization of transferrin receptors on DA terminals in the striatum has been suggested by studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (15) or MPTPtreated monkeys (16) and human brains taken at postmortem (15,16), but this still needs to be confirmed.…”

Section: Introductionmentioning

confidence: 99%

Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease.

Faucheux

Nillesse

Damier

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

195

101

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The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease.

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Distribution of ¹²⁵I‐Ferrotransferrin Binding Sites in the Mesencephalon of Control Subjects and Patients with Parkinson's Disease

Cited by 54 publications

References 22 publications

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Receptor-mediated Transcytosis of Lactoferrin through the Blood-Brain Barrier

Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease.

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Distribution of 125I‐Ferrotransferrin Binding Sites in the Mesencephalon of Control Subjects and Patients with Parkinson's Disease

Cited by 54 publications

References 22 publications

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Receptor-mediated Transcytosis of Lactoferrin through the Blood-Brain Barrier

Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease.

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Product

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Distribution of ¹²⁵I‐Ferrotransferrin Binding Sites in the Mesencephalon of Control Subjects and Patients with Parkinson's Disease