Metabolism and functions of copper in brain

doi:10.1016/j.pneurobio.2014.01.002

Progress in Neurobiology

Volume 116, May 2014, Pages 33-57

https://doi.org/10.1016/j.pneurobio.2014.01.002 Get rights and content

Highlights

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Copper is essential for brain functions.
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Excess of copper can cause oxidative stress.
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All proteins involved in copper homeostasis are expressed in brain.
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Astrocytes have the potential to take up, store and export copper.
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Disturbances of brain copper homeostasis are connected with neurodegeneration.

Abstract

Copper is an important trace element that is required for essential enzymes. However, due to its redox activity, copper can also lead to the generation of toxic reactive oxygen species. Therefore, cellular uptake, storage as well as export of copper have to be tightly regulated in order to guarantee sufficient copper supply for the synthesis of copper-containing enzymes but also to prevent copper-induced oxidative stress. In brain, copper is of importance for normal development. In addition, both copper deficiency as well as excess of copper can seriously affect brain functions. Therefore, this organ possesses ample mechanisms to regulate its copper metabolism. In brain, astrocytes are considered as important regulators of copper homeostasis. Impairments of homeostatic mechanisms in brain copper metabolism have been associated with neurodegeneration in human disorders such as Menkes disease, Wilson's disease and Alzheimer's disease. This review article will summarize the biological functions of copper in the brain and will describe the current knowledge on the mechanisms involved in copper transport, storage and export of brain cells. The role of copper in diseases that have been connected with disturbances in brain copper homeostasis will also be discussed.

Introduction

Copper is an indispensable element for all organisms that have an oxidative metabolism. Copper is after iron and zinc the third most abundant essential transition metal in human liver (Lewinska-Preis et al., 2011). Although some compounds exist with copper in the oxidation states Cu³⁺ and Cu⁴⁺, copper biochemistry is largely dominated by Cu⁺ and Cu²⁺ compounds, as these ions form numerous complexes with both organic and inorganic ligands. The soft Cu⁺ ion prefers ligands that have large polarizable electron clouds, such as sulfur ligands or unsaturated nitrogen donors. Such ligands usually exert coordination numbers from two to four with linear, trigonal or tetrahedral coordination, while the hard Cu²⁺ ion prefers sp³ hybridized nitrogen and oxygen ligands (Crichton and Pierre, 2001, Kaim and Rall, 1996, Rubino and Franz, 2012, Tisato et al., 2010, Wadas et al., 2007). The reduction potential of the Cu²⁺/Cu⁺ redox pair varies dramatically depending on the ligand environment and the pH. For example, the one electron oxidation of various Cu⁺-complexes toward dioxygen has been reported to vary between −1.5 and +1.3 V (Tisato et al., 2010), while in copper proteins the reduction potential for Cu²⁺/Cu⁺ ranges from +0.32 V to +0.78 V (Rubino and Franz, 2012).

The brain concentrates heavy metals including copper for metabolic use (Bush, 2000). Copper is of great importance for the normal development and function of the brain. As a cofactor of several enzymes and/or as structural component, copper is involved in many physiological pathways in the brain. This review will summarize the functions of copper in the brain for various biochemical pathways and will describe the current knowledge on the copper homeostasis by addressing copper transport, storage and export in brain cells. Finally, disturbances in the copper homeostasis that have been connected with neurodegenerative disorders will be discussed.

Section snippets

Importance of copper for brain function

Copper is utilized in the brain for general metabolic as well as for more brain specific functions (Lutsenko et al., 2010). Copper is an essential cofactor and/or a structural component of a number of important enzymes (Scheiber and Dringen, 2013) which are involved in redox reactions (Kaim and Rall, 1996, Rubino and Franz, 2012). The relatively high reduction potential of the Cu²⁺/Cu⁺ system enables many of the copper enzymes to directly oxidize their substrates, for example superoxide by

Copper uptake into the brain

Brain copper is derived from peripheral copper that is transported across the blood–brain barrier (BBB) and/or the blood–cerebrospinal fluid barrier (BCB), which separate the brain interstitial space from blood and cerebrospinal fluid (CSF), respectively (Zheng and Monnot, 2012). At both barriers copper is transported primarily as free ion (Choi and Zheng, 2009). Although the copper uptake into cerebral capillaries is much slower than into the choroid plexus, the copper acquired by cerebral

Astrocyte-neuron coupling in copper metabolism

Astrocytes, which constitute the main class of neuroglia, are the most abundant cells in the brain (Markiewicz and Lukomska, 2006, Sofroniew and Vinters, 2010). These cells are distributed throughout the entire brain and fulfill a range of important functions essential for brain physiology (Nedergaard et al., 2003, Parpura et al., 2012, Sofroniew and Vinters, 2010). Among other functions, astrocytes have been proposed to be involved in the control of brain extracellular ion homeostasis,

Copper and neurodegenerative diseases

Menkes and Wilson's disease (Kodama et al., 2011, Lorincz, 2010) are the best examples for pathological conditions that are connected with an impaired copper homeostasis that leads to neurodegeneration. While many of the clinical symptoms associated with the severe copper deficiency in Menkes disease can be attributed to a decrease in the activities of copper-dependent enzymes, copper toxicity in Wilson's disease is most likely a consequence of the redox activity of copper (Britton, 1996,

Conclusions and outlook

Within the last decade the knowledge on the metabolism and functions of copper in brain has dramatically increased. Most of the key players that are known to be involved in uptake, distribution, storage and export of copper in peripheral cell types and contribute to peripheral copper homeostasis are also present in brain cells. However, substantial parts of information on the function and the regulation of the various proteins that contribute to the copper metabolism of the different types of

Acknowledgments

Ivo F. Scheiber would like to thank the European Social Fund and the State Budget of the Czech Republic for financing (Project no. CZ.1.07/2.3.00/30.0061). Ralf Dringen and Julian Mercer would like to thank the Deakin University for financial support by the Thinkers in Residence Program.

References (608)

K.M. Acevedo et al.
Copper promotes the trafficking of the amyloid precursor protein
J. Biol. Chem.
(2011)
P.A. Adlard et al.
Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta
Neuron
(2008)
M.E. Aliaga et al.
Superoxide-dependent reduction of free Fe³⁺ and release of Fe²⁺ from ferritin by the physiologically-occurring Cu(I)-glutathione complex
Bioorg. Med. Chem.
(2011)
M.E. Aliaga et al.
Redox-active complexes formed during the interaction between glutathione and mercury and/or copper ions
J. Inorg. Biochem.
(2010)
S.G. Aller et al.
Eukaryotic CTR copper uptake transporters require two faces of the third transmembrane domain for helix packing, oligomerization, and function
J. Biol. Chem.
(2004)
K.E. Anderson
Huntington's disease
Handb. Clin. Neurol.
(2011)
G.K. Andrews
Regulation of metallothionein gene expression by oxidative stress and metal ions
Biochem. Pharmacol.
(2000)
T. Anezaki et al.
Expression of growth inhibitory factor (GIF) in normal and injured rat brains
Neurochem. Int.
(1995)
S.V. Antonyuk et al.
The structure of human extracellular copper–zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding
J. Mol. Biol.
(2009)
M. Aschner et al.
Metallothioneins in brain – the role in physiology and pathology
Toxicol. Appl. Pharmacol.
(1997)

I. Ascone et al.

An X-ray absorption study of the reconstitution process of bovine Cu,Zn superoxide dismutase by Cu(I)-glutathione complex

FEBS Lett.

(1993)

K. Balamurugan et al.

Copper homeostasis in eukaryotes: teetering on a tightrope

Biochim. Biophys. Acta

(2006)

C. Ballard et al.

Alzheimer's disease

Lancet

(2011)

N. Ballatori et al.

Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology

Mol. Aspects Med.

(2009)

L. Banci et al.

The different intermolecular interactions of the soluble copper-binding domains of the menkes protein, ATP7A

J. Biol. Chem.

(2007)

L. Banci et al.

An NMR study of the interaction of the N-terminal cytoplasmic tail of the Wilson disease protein with copper(I)-HAH1

J. Biol. Chem.

(2009)

L. Banci et al.

A structural–dynamical characterization of human Cox17

J. Biol. Chem.

(2008)

N. Barnes et al.

The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum

J. Biol. Chem.

(2005)

L.F. Barros et al.

Glucose and lactate supply to the synapse

Brain Res. Rev.

(2010)

M.H. Barros et al.

COX23, a homologue of COX17, is required for cytochrome oxidase assembly

J. Biol. Chem.

(2004)

A. Barthel et al.

Stimulation of phosphoinositide 3-kinase/Akt signaling by copper and zinc ions: mechanisms and consequences

Arch. Biochem. Biophys.

(2007)

J.S. Becker et al.

New mass spectrometric tools in brain research

TrAC Trends Anal. Chem.

(2010)

J. Beers et al.

Purification, characterization, and localization of yeast Cox17p, a mitochondrial copper shuttle

J. Biol. Chem.

(1997)

S.A. Bellingham et al.

Copper depletion down-regulates expression of the Alzheimer's disease amyloid-beta precursor protein gene

J. Biol. Chem.

(2004)

J.T. Bendor et al.

The function of α-synuclein

Neuron

(2013)

C.W. Berridge

Noradrenergic modulation of arousal

Brain Res. Rev.

(2008)

J. Bertinato et al.

Ctr1 transports silver into mammalian cells

J. Trace Elem. Med. Biol.

(2010)

J. Bertinato et al.

Copper modulates the degradation of copper chaperone for Cu,Zn superoxide dismutase by the 26 S proteosome

J. Biol. Chem.

(2003)

Y.M. Bordelon

Clinical neurogenetics: Huntington disease

Neurol. Clin.

(2013)

V.B. Borisov

Defects in mitochondrial respiratory complexes III and IV, and human pathologies

Mol. Aspects Med.

(2002)

Y. Boulanger et al.

¹¹³Cd NMR study of a metallothionein fragment. Evidence for a two-domain structure

J. Biol. Chem.

(1982)

D. Bousquet-Moore et al.

Interactions of peptide amidation and copper: novel biomarkers and mechanisms of neural dysfunction

Neurobiol. Dis.

(2010)

M.W. Brazier et al.

Manganese binding to the prion protein

J. Biol. Chem.

(2008)

D.R. Brown

Role of the prion protein in copper turnover in astrocytes

Neurobiol. Dis.

(2004)

R.H. Buhler et al.

Human hepatic metallothioneins

FEBS Lett.

(1974)

M.J. Burkitt

A critical overview of the chemistry of copper-dependent low density lipoprotein oxidation: roles of lipid hydroperoxides, alpha-tocopherol, thiols, and ceruloplasmin

Arch. Biochem. Biophys.

(2001)

A.I. Bush

Metals and neuroscience

Curr. Opin. Chem. Biol.

(2000)

J. Camakaris et al.

Molecular mechanisms of copper homeostasis

Biochem. Biophys. Res. Commun.

(1999)

T. Canello et al.

Copper is toxic to PrP-ablated mice and exacerbates disease in a mouse model of E200K genetic prion disease

Neurobiol. Dis.

(2012)

H.S. Carr et al.

Yeast Cox11, a protein essential for cytochrome c oxidase assembly, is a Cu(I)-binding protein

J. Biol. Chem.

(2002)

R.J. Carrico et al.

The presence of zinc in human cytocuprein and some properties of the apoprotein

J. Biol. Chem.

(1970)

A.L. Caruano-Yzermans et al.

Mechanisms of the copper-dependent turnover of the copper chaperone for superoxide dismutase

J. Biol. Chem.

(2006)

R.L. Casareno et al.

The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase

J. Biol. Chem.

(1998)

R.J. Castellani et al.

Alzheimer disease

Dis. Mon.

(2010)

I. Acquatella-Tran Van Ba et al.

From prion diseases to prion-like propagation mechanisms of neurodegenerative diseases

Int. J. Cell Biol.

(2013)

J.D. Adams et al.

Alzheimer's and Parkinson's disease. Brain levels of glutathione, glutathione disulfide, and vitamin E

Mol. Chem. Neuropathol.

(1991)

A. Aguzzi et al.

The prion's elusive reason for being

Annu. Rev. Neurosci.

(2008)

M. Alcaraz-Zubeldia et al.

Copper sulfate prevents tyrosine hydroxylase reduced activity and motor deficits in a Parkinson's disease model in mice

Rev. Invest. Clin.

(2009)

M. Alcaraz-Zubeldia et al.

Neuroprotective effect of acute and chronic administration of copper (II) sulfate against MPP⁺ neurotoxicity in mice

Neurochem. Res.

(2001)

S.G. Aller et al.

Projection structure of the human copper transporter CTR1 at 6-A resolution reveals a compact trimer with a novel channel-like architecture

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

(2006)

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View full text

Metabolism and functions of copper in brain

Highlights

Abstract

Introduction

Section snippets

Importance of copper for brain function

Copper uptake into the brain

Astrocyte-neuron coupling in copper metabolism

Copper and neurodegenerative diseases

Conclusions and outlook

Acknowledgments

J. Biol. Chem.

Neuron

Bioorg. Med. Chem.

J. Inorg. Biochem.

J. Biol. Chem.

Handb. Clin. Neurol.

Biochem. Pharmacol.

Neurochem. Int.

J. Mol. Biol.

Toxicol. Appl. Pharmacol.

FEBS Lett.

Biochim. Biophys. Acta

Lancet

Mol. Aspects Med.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Brain Res. Rev.

J. Biol. Chem.

Arch. Biochem. Biophys.

TrAC Trends Anal. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Brain Res. Rev.

J. Trace Elem. Med. Biol.

J. Biol. Chem.

Neurol. Clin.

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Neurobiol. Dis.

J. Biol. Chem.

Neurobiol. Dis.

FEBS Lett.

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Curr. Opin. Chem. Biol.

Biochem. Biophys. Res. Commun.

Neurobiol. Dis.

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J. Biol. Chem.

J. Biol. Chem.

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