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In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution

View Article: PubMed Central - PubMed

ABSTRACT

Essential elements as copper and iron modulate a wide range of physiological functions. Their metabolism is strictly regulated by cellular pathways, since dysregulation of metal homeostasis is responsible for many detrimental effects. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and prion diseases are characterized by alterations of metal ions. These neurodegenerative maladies involve proteins that bind metals and mediate their metabolism through not well-defined mechanisms. Prion protein, for instance, interacts with divalent cations via multiple metal-binding sites and it modulates several metal-dependent physiological functions, such as S-nitrosylation of NMDA receptors. In this work we focused on the effect of prion protein absence on copper and iron metabolism during development and adulthood. In particular, we investigated copper and iron functional values in serum and several organs such as liver, spleen, total brain and isolated hippocampus. Our results show that iron content is diminished in prion protein- mouse serum, while it accumulates in liver and spleen. Our data suggest that these alterations can be due to impairments in copper-dependent cerulopalsmin activity which is known to affect iron mobilization. In prion protein- mouse total brain and hippocampus, metal ion content shows a fluctuating trend, suggesting the presence of homeostatic compensatory mechanisms. However, copper and iron functional values are likely altered also in these two organs, as indicated by the modulation of metal-binding protein expression levels. Altogether, these results reveal that the absence of the cellular prion protein impairs copper metabolism and copper-dependent oxidase activity, with ensuing alteration of iron mobilization from cellular storage compartments.

No MeSH data available.


Related in: MedlinePlus

Proposed model for PrPC role in copper and iron homeostasis. Wild-type PrPC mouse. In both liver and spleen, PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool, reduce to Cu+ and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, in the liver, PrPC may be involved in the transport of copper to the TGN where Atp7b load it on Cp. Hence, holo-Cp can be released in the serum or GPI-anchored on hepatocytes, thus mediating iron export through its copper-dependent ferroxidase activity. PrPC- mice. In the absence of PrPC, liver copper uptake is affected, hence the formation of holo-Cp is diminished. Consequently, iron is accumulated in the liver, TfR1 level is decreased, while FtH and FtL levels are increased. Therefore, hepcidin secretion is enhanced, with ensuing block of Fpn1. In the spleen, the absence of PrPC induces a reduction in copper uptake that, together with hepcidin-mediated Fpn1 block, triggers iron accumulation, that, in turn, leads to splenomegaly. Liver and spleen iron accumulation results in decreased serum iron content. Wild-type PrPC CNS. PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool and reduce to Cu+, and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, PrPC may be involved in the intracellular transport of copper, and loading on Ccs. PrPC- mouse CNS. In PrPC- blood, iron and Cp-bound copper levels are decreased. Therefore, compensatory mechanism maintain physiological copper and iron levels. In both total brain and isolated hippocampus, Tf, TfR1, FtH, FtL are modulated in response to iron deficiency. Copper-binding protein Ctr1, Atp7a and Cp are modulated in the hippocampus, responding to copper deficiency. Ccs is decreased in PrPC- CNS, likely causing the decrease in Sod1 activity (Brown and Besinger, 1998; Kralovicova et al., 2009). All the alterations observed in PrPC- mouse have been reported as big arrows pointing up in case of increase, pointing down in case of decrease. In the CNS scheme, *flanking the arrow indicates an alteration observed only in the isolated hippocampus, but not in the total brain.
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Figure 6: Proposed model for PrPC role in copper and iron homeostasis. Wild-type PrPC mouse. In both liver and spleen, PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool, reduce to Cu+ and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, in the liver, PrPC may be involved in the transport of copper to the TGN where Atp7b load it on Cp. Hence, holo-Cp can be released in the serum or GPI-anchored on hepatocytes, thus mediating iron export through its copper-dependent ferroxidase activity. PrPC- mice. In the absence of PrPC, liver copper uptake is affected, hence the formation of holo-Cp is diminished. Consequently, iron is accumulated in the liver, TfR1 level is decreased, while FtH and FtL levels are increased. Therefore, hepcidin secretion is enhanced, with ensuing block of Fpn1. In the spleen, the absence of PrPC induces a reduction in copper uptake that, together with hepcidin-mediated Fpn1 block, triggers iron accumulation, that, in turn, leads to splenomegaly. Liver and spleen iron accumulation results in decreased serum iron content. Wild-type PrPC CNS. PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool and reduce to Cu+, and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, PrPC may be involved in the intracellular transport of copper, and loading on Ccs. PrPC- mouse CNS. In PrPC- blood, iron and Cp-bound copper levels are decreased. Therefore, compensatory mechanism maintain physiological copper and iron levels. In both total brain and isolated hippocampus, Tf, TfR1, FtH, FtL are modulated in response to iron deficiency. Copper-binding protein Ctr1, Atp7a and Cp are modulated in the hippocampus, responding to copper deficiency. Ccs is decreased in PrPC- CNS, likely causing the decrease in Sod1 activity (Brown and Besinger, 1998; Kralovicova et al., 2009). All the alterations observed in PrPC- mouse have been reported as big arrows pointing up in case of increase, pointing down in case of decrease. In the CNS scheme, *flanking the arrow indicates an alteration observed only in the isolated hippocampus, but not in the total brain.

Mentions: The results we obtained led us to hypothesize the model described in Figure 6. PrPC absence causes a serum anemia with a subsequent accumulation in the liver and spleen. No differences in total copper content were observed in the serum and in the liver, but oxidase activity of the copper-dependent Cp was lower in PrPC- mice compared to wild-type. The reduction in Cp activity is likely due to altered incorporation of copper into Cp with the subsequent formation of apo-Cp which is more prone to degradation (Hellman and Gitlin, 2002). The diminished oxidase activity affects Fe2+ to Fe3+ oxidation, thus impairing iron release from stores and its incorporation into Tf. The atypical behavior of iron and iron-binding proteins in the spleen may be due to the concurrent copper reduction in PrPC- spleen (Auclair et al., 2006; Andersen et al., 2007).


In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution
Proposed model for PrPC role in copper and iron homeostasis. Wild-type PrPC mouse. In both liver and spleen, PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool, reduce to Cu+ and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, in the liver, PrPC may be involved in the transport of copper to the TGN where Atp7b load it on Cp. Hence, holo-Cp can be released in the serum or GPI-anchored on hepatocytes, thus mediating iron export through its copper-dependent ferroxidase activity. PrPC- mice. In the absence of PrPC, liver copper uptake is affected, hence the formation of holo-Cp is diminished. Consequently, iron is accumulated in the liver, TfR1 level is decreased, while FtH and FtL levels are increased. Therefore, hepcidin secretion is enhanced, with ensuing block of Fpn1. In the spleen, the absence of PrPC induces a reduction in copper uptake that, together with hepcidin-mediated Fpn1 block, triggers iron accumulation, that, in turn, leads to splenomegaly. Liver and spleen iron accumulation results in decreased serum iron content. Wild-type PrPC CNS. PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool and reduce to Cu+, and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, PrPC may be involved in the intracellular transport of copper, and loading on Ccs. PrPC- mouse CNS. In PrPC- blood, iron and Cp-bound copper levels are decreased. Therefore, compensatory mechanism maintain physiological copper and iron levels. In both total brain and isolated hippocampus, Tf, TfR1, FtH, FtL are modulated in response to iron deficiency. Copper-binding protein Ctr1, Atp7a and Cp are modulated in the hippocampus, responding to copper deficiency. Ccs is decreased in PrPC- CNS, likely causing the decrease in Sod1 activity (Brown and Besinger, 1998; Kralovicova et al., 2009). All the alterations observed in PrPC- mouse have been reported as big arrows pointing up in case of increase, pointing down in case of decrease. In the CNS scheme, *flanking the arrow indicates an alteration observed only in the isolated hippocampus, but not in the total brain.
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Related In: Results  -  Collection

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Figure 6: Proposed model for PrPC role in copper and iron homeostasis. Wild-type PrPC mouse. In both liver and spleen, PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool, reduce to Cu+ and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, in the liver, PrPC may be involved in the transport of copper to the TGN where Atp7b load it on Cp. Hence, holo-Cp can be released in the serum or GPI-anchored on hepatocytes, thus mediating iron export through its copper-dependent ferroxidase activity. PrPC- mice. In the absence of PrPC, liver copper uptake is affected, hence the formation of holo-Cp is diminished. Consequently, iron is accumulated in the liver, TfR1 level is decreased, while FtH and FtL levels are increased. Therefore, hepcidin secretion is enhanced, with ensuing block of Fpn1. In the spleen, the absence of PrPC induces a reduction in copper uptake that, together with hepcidin-mediated Fpn1 block, triggers iron accumulation, that, in turn, leads to splenomegaly. Liver and spleen iron accumulation results in decreased serum iron content. Wild-type PrPC CNS. PrPC may bind Cu2+ released from the blood Cu2+ exchangeable pool and reduce to Cu+, and pass it to Ctr1 for its uptake, or may function itself as a transporter by internalization. Therefore, PrPC may be involved in the intracellular transport of copper, and loading on Ccs. PrPC- mouse CNS. In PrPC- blood, iron and Cp-bound copper levels are decreased. Therefore, compensatory mechanism maintain physiological copper and iron levels. In both total brain and isolated hippocampus, Tf, TfR1, FtH, FtL are modulated in response to iron deficiency. Copper-binding protein Ctr1, Atp7a and Cp are modulated in the hippocampus, responding to copper deficiency. Ccs is decreased in PrPC- CNS, likely causing the decrease in Sod1 activity (Brown and Besinger, 1998; Kralovicova et al., 2009). All the alterations observed in PrPC- mouse have been reported as big arrows pointing up in case of increase, pointing down in case of decrease. In the CNS scheme, *flanking the arrow indicates an alteration observed only in the isolated hippocampus, but not in the total brain.
Mentions: The results we obtained led us to hypothesize the model described in Figure 6. PrPC absence causes a serum anemia with a subsequent accumulation in the liver and spleen. No differences in total copper content were observed in the serum and in the liver, but oxidase activity of the copper-dependent Cp was lower in PrPC- mice compared to wild-type. The reduction in Cp activity is likely due to altered incorporation of copper into Cp with the subsequent formation of apo-Cp which is more prone to degradation (Hellman and Gitlin, 2002). The diminished oxidase activity affects Fe2+ to Fe3+ oxidation, thus impairing iron release from stores and its incorporation into Tf. The atypical behavior of iron and iron-binding proteins in the spleen may be due to the concurrent copper reduction in PrPC- spleen (Auclair et al., 2006; Andersen et al., 2007).

View Article: PubMed Central - PubMed

ABSTRACT

Essential elements as copper and iron modulate a wide range of physiological functions. Their metabolism is strictly regulated by cellular pathways, since dysregulation of metal homeostasis is responsible for many detrimental effects. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and prion diseases are characterized by alterations of metal ions. These neurodegenerative maladies involve proteins that bind metals and mediate their metabolism through not well-defined mechanisms. Prion protein, for instance, interacts with divalent cations via multiple metal-binding sites and it modulates several metal-dependent physiological functions, such as S-nitrosylation of NMDA receptors. In this work we focused on the effect of prion protein absence on copper and iron metabolism during development and adulthood. In particular, we investigated copper and iron functional values in serum and several organs such as liver, spleen, total brain and isolated hippocampus. Our results show that iron content is diminished in prion protein- mouse serum, while it accumulates in liver and spleen. Our data suggest that these alterations can be due to impairments in copper-dependent cerulopalsmin activity which is known to affect iron mobilization. In prion protein- mouse total brain and hippocampus, metal ion content shows a fluctuating trend, suggesting the presence of homeostatic compensatory mechanisms. However, copper and iron functional values are likely altered also in these two organs, as indicated by the modulation of metal-binding protein expression levels. Altogether, these results reveal that the absence of the cellular prion protein impairs copper metabolism and copper-dependent oxidase activity, with ensuing alteration of iron mobilization from cellular storage compartments.

No MeSH data available.


Related in: MedlinePlus