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Iron and neurodegeneration: from cellular homeostasis to disease.

Batista-Nascimento L, Pimentel C, Menezes RA, Rodrigues-Pousada C - Oxid Med Cell Longev (2012)

Bottom Line: Other conditions, such as Friedreich's ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation.Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death.Saccharomyces cerevisiae, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, EAN, Oeiras, Portugal.

ABSTRACT
Accumulation of iron (Fe) is often detected in the brains of people suffering from neurodegenerative diseases. High Fe concentrations have been consistently observed in Parkinson's, Alzheimer's, and Huntington's diseases; however, it is not clear whether this Fe contributes to the progression of these diseases. Other conditions, such as Friedreich's ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation. Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death. The characterization of the mechanisms involved in the misregulation of Fe in the brain is crucial to understand the pathology of the neurodegenerative disorders and develop new therapeutic strategies. Saccharomyces cerevisiae, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology.

Show MeSH

Related in: MedlinePlus

The brain iron homeostasis. Iron (Fe) binds to transferrin (Tf), enters the brain through the transferrin receptors (TfR) by endocytosis, and translocates across the endosomal membrane through the divalent metal transporter 1 (DMT1). Lactoferrin receptors (LfR) provide another pathway to transport Fe from Fe containing lactoferrin across the cell membranes. Inside the cell Fe binds to H-ferritin and accumulates around the neuromelanin. Ferroportin (Fpn) transports Fe2+ outside the neuron that is oxidized to Fe3+ by ceruloplasmin promoting its binding to Tf.
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fig1: The brain iron homeostasis. Iron (Fe) binds to transferrin (Tf), enters the brain through the transferrin receptors (TfR) by endocytosis, and translocates across the endosomal membrane through the divalent metal transporter 1 (DMT1). Lactoferrin receptors (LfR) provide another pathway to transport Fe from Fe containing lactoferrin across the cell membranes. Inside the cell Fe binds to H-ferritin and accumulates around the neuromelanin. Ferroportin (Fpn) transports Fe2+ outside the neuron that is oxidized to Fe3+ by ceruloplasmin promoting its binding to Tf.

Mentions: The Fe uptake pathway starts in the intestines, where Fe3+ is reduced to Fe2+ that then is transported to the blood by Fpn. In the blood, Cp oxidizes Fe2+ to Fe3+ and promotes its binding to the serum iron carrier, Tf [19]. In order to enter the brain, Fe needs to cross two distinct barriers, the BBB and BCSF (blood-cerebrospinal fluid) [20]. The most common pathway for Fe transference across the BBB is through the TfRs expressed in the endothelial cells. The circulating Fe bound to Tf is captured by TfR, entering the brain by endocytosis and then is translocated across the endosomal membrane, probably through the divalent metal transporter 1 (DMT1) [21]. In addition to the Tf-TfR pathway, it has been suggested that the lactoferrin receptor-lactoferrin (LfR-Lf) pathway might also play a role in Fe transport across the BBB. Fe2+ in the cytoplasm can also be transported inside the mitochondria by mitoferrin or participate in electron exchange reactions [22, 23]. Figure 1 summarizes the brain Fe uptake pathways.


Iron and neurodegeneration: from cellular homeostasis to disease.

Batista-Nascimento L, Pimentel C, Menezes RA, Rodrigues-Pousada C - Oxid Med Cell Longev (2012)

The brain iron homeostasis. Iron (Fe) binds to transferrin (Tf), enters the brain through the transferrin receptors (TfR) by endocytosis, and translocates across the endosomal membrane through the divalent metal transporter 1 (DMT1). Lactoferrin receptors (LfR) provide another pathway to transport Fe from Fe containing lactoferrin across the cell membranes. Inside the cell Fe binds to H-ferritin and accumulates around the neuromelanin. Ferroportin (Fpn) transports Fe2+ outside the neuron that is oxidized to Fe3+ by ceruloplasmin promoting its binding to Tf.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369498&req=5

fig1: The brain iron homeostasis. Iron (Fe) binds to transferrin (Tf), enters the brain through the transferrin receptors (TfR) by endocytosis, and translocates across the endosomal membrane through the divalent metal transporter 1 (DMT1). Lactoferrin receptors (LfR) provide another pathway to transport Fe from Fe containing lactoferrin across the cell membranes. Inside the cell Fe binds to H-ferritin and accumulates around the neuromelanin. Ferroportin (Fpn) transports Fe2+ outside the neuron that is oxidized to Fe3+ by ceruloplasmin promoting its binding to Tf.
Mentions: The Fe uptake pathway starts in the intestines, where Fe3+ is reduced to Fe2+ that then is transported to the blood by Fpn. In the blood, Cp oxidizes Fe2+ to Fe3+ and promotes its binding to the serum iron carrier, Tf [19]. In order to enter the brain, Fe needs to cross two distinct barriers, the BBB and BCSF (blood-cerebrospinal fluid) [20]. The most common pathway for Fe transference across the BBB is through the TfRs expressed in the endothelial cells. The circulating Fe bound to Tf is captured by TfR, entering the brain by endocytosis and then is translocated across the endosomal membrane, probably through the divalent metal transporter 1 (DMT1) [21]. In addition to the Tf-TfR pathway, it has been suggested that the lactoferrin receptor-lactoferrin (LfR-Lf) pathway might also play a role in Fe transport across the BBB. Fe2+ in the cytoplasm can also be transported inside the mitochondria by mitoferrin or participate in electron exchange reactions [22, 23]. Figure 1 summarizes the brain Fe uptake pathways.

Bottom Line: Other conditions, such as Friedreich's ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation.Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death.Saccharomyces cerevisiae, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, EAN, Oeiras, Portugal.

ABSTRACT
Accumulation of iron (Fe) is often detected in the brains of people suffering from neurodegenerative diseases. High Fe concentrations have been consistently observed in Parkinson's, Alzheimer's, and Huntington's diseases; however, it is not clear whether this Fe contributes to the progression of these diseases. Other conditions, such as Friedreich's ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation. Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death. The characterization of the mechanisms involved in the misregulation of Fe in the brain is crucial to understand the pathology of the neurodegenerative disorders and develop new therapeutic strategies. Saccharomyces cerevisiae, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology.

Show MeSH
Related in: MedlinePlus