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Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis.

Telianidis J, Hung YH, Materia S, Fontaine SL - Front Aging Neurosci (2013)

Bottom Line: Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993.Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders.Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia ; Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia.

ABSTRACT
Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram illustrating the proposed mechanisms of copper transport across the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB).(A) Copper transport under physiological conditions. Copper import into cells is via the major copper import protein CTR1. The proposed locations and orientation of ATP7A and ATP7B are shown. ATP7A is expressed in cerebrovascular endothelial cells that form the BBB but its expression is 3.4-fold higher in the choroid plexus than in the cerebral capillaries. In both choroid plexus epithelial cells and capillary endothelial cells of the brain, ATP7A predominantly localizes to the basolateral membrane. ATP7A facilitates copper transport from the blood across the BBB to the brain parenchyma. At the choroid plexus, ATP7A facilitates the removal of excess copper from the brain into the blood. Therefore, the BCB serves as the main pathway for eliminating excess brain copper. In contrast, ATP7B is concentrated at the apical membrane. At the CSF-facing apical membrane of choroid plexus epithelial cells, ATP7B may contribute to copper transport into the CSF and copper sequestration in the choroid plexus. Astrocytes are the first brain parenchyma cells to encounter metal ions that cross the BBB and play an important role in copper transport from the blood and CSF toward neurons. Copper transport in glutamatergic neurons is depicted. Copper-independent and reversible trafficking of ATP7A is stimulated by N-methyl-D-aspartate receptor (NMDAR) activation that leads to Ca2+ influx and is associated with the rapid release of copper from neurons. The released copper down-regulates NMDAR activity thus protecting neurons from excitotoxicity. (B) Perturbed copper transport in Menkes disease due to the absence or inactivation of ATP7A. The predicted consequences of ATP7A inactivation in relation to copper levels in brain barrier cells, astrocytes and neurons are shown. Any copper that reaches the BBB accumulates within endothelial cells leading to reduced copper transport to the brain parenchyma, astrocytes and neurons. Any copper that reaches astrocytes also will accumulate. There is reduced copper transport across the BCB. Excitotoxicity due to impaired synaptic copper release from glutamatergic neurons, which down-regulates NMDAR activity, can contribute to seizures and neuronal degeneration in Menkes disease.
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Figure 2: Schematic diagram illustrating the proposed mechanisms of copper transport across the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB).(A) Copper transport under physiological conditions. Copper import into cells is via the major copper import protein CTR1. The proposed locations and orientation of ATP7A and ATP7B are shown. ATP7A is expressed in cerebrovascular endothelial cells that form the BBB but its expression is 3.4-fold higher in the choroid plexus than in the cerebral capillaries. In both choroid plexus epithelial cells and capillary endothelial cells of the brain, ATP7A predominantly localizes to the basolateral membrane. ATP7A facilitates copper transport from the blood across the BBB to the brain parenchyma. At the choroid plexus, ATP7A facilitates the removal of excess copper from the brain into the blood. Therefore, the BCB serves as the main pathway for eliminating excess brain copper. In contrast, ATP7B is concentrated at the apical membrane. At the CSF-facing apical membrane of choroid plexus epithelial cells, ATP7B may contribute to copper transport into the CSF and copper sequestration in the choroid plexus. Astrocytes are the first brain parenchyma cells to encounter metal ions that cross the BBB and play an important role in copper transport from the blood and CSF toward neurons. Copper transport in glutamatergic neurons is depicted. Copper-independent and reversible trafficking of ATP7A is stimulated by N-methyl-D-aspartate receptor (NMDAR) activation that leads to Ca2+ influx and is associated with the rapid release of copper from neurons. The released copper down-regulates NMDAR activity thus protecting neurons from excitotoxicity. (B) Perturbed copper transport in Menkes disease due to the absence or inactivation of ATP7A. The predicted consequences of ATP7A inactivation in relation to copper levels in brain barrier cells, astrocytes and neurons are shown. Any copper that reaches the BBB accumulates within endothelial cells leading to reduced copper transport to the brain parenchyma, astrocytes and neurons. Any copper that reaches astrocytes also will accumulate. There is reduced copper transport across the BCB. Excitotoxicity due to impaired synaptic copper release from glutamatergic neurons, which down-regulates NMDAR activity, can contribute to seizures and neuronal degeneration in Menkes disease.

Mentions: The ATP7A gene is transcribed to produce an 8.5 kb transcript that is expressed in all tissues examined except for the liver (Chelly et al., 1993; Vulpe et al., 1993). In the mouse brain, the Atp7a transcript is expressed in the cerebrovascular endothelial (CVE) cells that form the BBB (Qian et al., 1998), and is strongly expressed in the choroid plexus (Kuo et al., 1997; Murata et al., 1997; Nishihara et al., 1998; Choi and Zheng, 2009), a structure that forms the BCB and regulates the concentration of substances in the CSF (Figure 2A). Choi and Zheng (2009) further showed that Atp7a is more highly expressed in the brain barriers (BBB and BCB), the brain capillaries and choroid plexus, than in brain parenchyma. Comparing the two barriers, Atp7a mRNA expression is 3.4-fold higher in the choroid plexus than in the cerebral capillaries. This observation is consistent with the finding that the Atp7a protein levels in the developing and adult mouse brain are highest in the choroid plexus/ependymal cells of the lateral and third ventricles (Niciu et al., 2006).


Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis.

Telianidis J, Hung YH, Materia S, Fontaine SL - Front Aging Neurosci (2013)

Schematic diagram illustrating the proposed mechanisms of copper transport across the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB).(A) Copper transport under physiological conditions. Copper import into cells is via the major copper import protein CTR1. The proposed locations and orientation of ATP7A and ATP7B are shown. ATP7A is expressed in cerebrovascular endothelial cells that form the BBB but its expression is 3.4-fold higher in the choroid plexus than in the cerebral capillaries. In both choroid plexus epithelial cells and capillary endothelial cells of the brain, ATP7A predominantly localizes to the basolateral membrane. ATP7A facilitates copper transport from the blood across the BBB to the brain parenchyma. At the choroid plexus, ATP7A facilitates the removal of excess copper from the brain into the blood. Therefore, the BCB serves as the main pathway for eliminating excess brain copper. In contrast, ATP7B is concentrated at the apical membrane. At the CSF-facing apical membrane of choroid plexus epithelial cells, ATP7B may contribute to copper transport into the CSF and copper sequestration in the choroid plexus. Astrocytes are the first brain parenchyma cells to encounter metal ions that cross the BBB and play an important role in copper transport from the blood and CSF toward neurons. Copper transport in glutamatergic neurons is depicted. Copper-independent and reversible trafficking of ATP7A is stimulated by N-methyl-D-aspartate receptor (NMDAR) activation that leads to Ca2+ influx and is associated with the rapid release of copper from neurons. The released copper down-regulates NMDAR activity thus protecting neurons from excitotoxicity. (B) Perturbed copper transport in Menkes disease due to the absence or inactivation of ATP7A. The predicted consequences of ATP7A inactivation in relation to copper levels in brain barrier cells, astrocytes and neurons are shown. Any copper that reaches the BBB accumulates within endothelial cells leading to reduced copper transport to the brain parenchyma, astrocytes and neurons. Any copper that reaches astrocytes also will accumulate. There is reduced copper transport across the BCB. Excitotoxicity due to impaired synaptic copper release from glutamatergic neurons, which down-regulates NMDAR activity, can contribute to seizures and neuronal degeneration in Menkes disease.
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Related In: Results  -  Collection

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Figure 2: Schematic diagram illustrating the proposed mechanisms of copper transport across the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB).(A) Copper transport under physiological conditions. Copper import into cells is via the major copper import protein CTR1. The proposed locations and orientation of ATP7A and ATP7B are shown. ATP7A is expressed in cerebrovascular endothelial cells that form the BBB but its expression is 3.4-fold higher in the choroid plexus than in the cerebral capillaries. In both choroid plexus epithelial cells and capillary endothelial cells of the brain, ATP7A predominantly localizes to the basolateral membrane. ATP7A facilitates copper transport from the blood across the BBB to the brain parenchyma. At the choroid plexus, ATP7A facilitates the removal of excess copper from the brain into the blood. Therefore, the BCB serves as the main pathway for eliminating excess brain copper. In contrast, ATP7B is concentrated at the apical membrane. At the CSF-facing apical membrane of choroid plexus epithelial cells, ATP7B may contribute to copper transport into the CSF and copper sequestration in the choroid plexus. Astrocytes are the first brain parenchyma cells to encounter metal ions that cross the BBB and play an important role in copper transport from the blood and CSF toward neurons. Copper transport in glutamatergic neurons is depicted. Copper-independent and reversible trafficking of ATP7A is stimulated by N-methyl-D-aspartate receptor (NMDAR) activation that leads to Ca2+ influx and is associated with the rapid release of copper from neurons. The released copper down-regulates NMDAR activity thus protecting neurons from excitotoxicity. (B) Perturbed copper transport in Menkes disease due to the absence or inactivation of ATP7A. The predicted consequences of ATP7A inactivation in relation to copper levels in brain barrier cells, astrocytes and neurons are shown. Any copper that reaches the BBB accumulates within endothelial cells leading to reduced copper transport to the brain parenchyma, astrocytes and neurons. Any copper that reaches astrocytes also will accumulate. There is reduced copper transport across the BCB. Excitotoxicity due to impaired synaptic copper release from glutamatergic neurons, which down-regulates NMDAR activity, can contribute to seizures and neuronal degeneration in Menkes disease.
Mentions: The ATP7A gene is transcribed to produce an 8.5 kb transcript that is expressed in all tissues examined except for the liver (Chelly et al., 1993; Vulpe et al., 1993). In the mouse brain, the Atp7a transcript is expressed in the cerebrovascular endothelial (CVE) cells that form the BBB (Qian et al., 1998), and is strongly expressed in the choroid plexus (Kuo et al., 1997; Murata et al., 1997; Nishihara et al., 1998; Choi and Zheng, 2009), a structure that forms the BCB and regulates the concentration of substances in the CSF (Figure 2A). Choi and Zheng (2009) further showed that Atp7a is more highly expressed in the brain barriers (BBB and BCB), the brain capillaries and choroid plexus, than in brain parenchyma. Comparing the two barriers, Atp7a mRNA expression is 3.4-fold higher in the choroid plexus than in the cerebral capillaries. This observation is consistent with the finding that the Atp7a protein levels in the developing and adult mouse brain are highest in the choroid plexus/ependymal cells of the lateral and third ventricles (Niciu et al., 2006).

Bottom Line: Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993.Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders.Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia ; Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia.

ABSTRACT
Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

No MeSH data available.


Related in: MedlinePlus