copper and the brain

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Copper and Iron Disordersof the BrainErik Madsen and Jonathan D. GitlinEdward Mallinckrodt Department of Pediatrics, Washington UniversitySchool of Medicine, St. Louis, Missouri 63130; email: [email protected],[email protected]

Annu. Rev. Neurosci. 2007. 30:317–37

First published online as a Review in Advance onMarch 16, 2007

The Annual Review of Neuroscience is online atneuro.annualreviews.org

This article’s doi:10.1146/annurev.neuro.30.051606.094232

Copyright c© 2007 by Annual Reviews.All rights reserved

0147-006X/07/0721-0317$20.00

Key Words

p-type Atpase, Golgi, ferroxidase, astrocyte, blood-brain barrier,neurodegeneration

AbstractCopper and iron are transition elements essential for life. Thesemetals are required to maintain the brain’s biochemistry such thatdeficiency or excess of either copper or iron results in central nervoussystem disease. This review focuses on the inherited disorders in hu-mans that directly affect copper or iron homeostasis in the brain.Elucidation of the molecular genetic basis of these rare disordershas provided insight into the mechanisms of copper and iron acqui-sition, trafficking, storage, and excretion in the brain. This knowl-edge permits a greater understanding of copper and iron roles inneurobiology and neurologic disease and may allow for the develop-ment of therapeutic approaches where aberrant metal homeostasisis implicated in disease pathogenesis.

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Contents

INTRODUCTION. . . . . . . . . . . . . . . . . 318COPPER . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

Overview . . . . . . . . . . . . . . . . . . . . . . . . 318Copper Metabolism . . . . . . . . . . . . . . 319Menkes Disease . . . . . . . . . . . . . . . . . . 322Wilson Disease . . . . . . . . . . . . . . . . . . . 323

IRON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324Overview . . . . . . . . . . . . . . . . . . . . . . . . 324Iron Metabolism . . . . . . . . . . . . . . . . . 325Aceruloplasminemia . . . . . . . . . . . . . . 327Neuroferritinopathy . . . . . . . . . . . . . . 328Friedreich’s Ataxia . . . . . . . . . . . . . . . . 329Neurodegeneration with Brain

Iron Accumulation . . . . . . . . . . . . 329CONCLUSIONS. . . . . . . . . . . . . . . . . . . 329

INTRODUCTION

Copper and iron function as cofactors inspecific proteins, catalyzing electron trans-fer reactions required for cellular metabolismand binding inorganic ions (e.g., oxygen)that serve as substrates for this biochemistry(Andrews & Schmidt 2006, Balamurugan &Schaffner 2006). Deficiency in these met-als results in metabolic abnormalities due toloss of function of these iron- and copper-dependent proteins. Excess of these metalscan result in the unregulated oxidation of pro-teins, lipids, and other cellular componentscausing subsequent tissue injury. Thus path-ways of copper and iron metabolism haveevolved to ensure adequate amounts of eachmetal for cellular survival while protecting theorganism from the consequences of metal ex-cess. In the past decade, elucidation of the ge-netic basis of many of the inherited copper andiron metabolism disorders has begun to pro-vide insight into these pathways, permittingan understanding of the mechanisms involvedin cellular homeostasis of these metals.

The inherited copper and iron metabolismdisorders that cause deficiency or excess ofthese metals in the brain result in central ner-vous system disease (Ponka 2004, Waggoner

et al. 1999). Although these disorders revealthat copper and iron homeostasis is essen-tial for normal brain function, little is cur-rently known about the mechanisms of copperand iron acquisition, trafficking, storage, andexcretion within the central nervous system.How and where are iron and copper storedin the brain and under which circumstancesdo these metals accumulate? How do cells inthe brain acquire these metals when needed?Why is iron deficiency in utero associated withsignificant long-term cognitive impairment?How are the uptake and excretion of thesemetals regulated in the brain, and what is therelationship to these processes in systemic cir-culation? How does excess copper accumu-lation within the brain result in psychiatricdisease? Does impaired homeostasis of cop-per or iron contribute to the pathogenesis ofcommon neurodegenerative disorders such asParkinson or Alzheimer disease? One only hasto view the clinical consequences of accumu-lation or deficiency of these metals in the hu-man brain to appreciate the critical nature ofsuch questions. Mechanistic understanding ofthe human genetic disorders that impair cop-per or iron homeostasis in the brain providesinsight into the role of these metals in neuro-biology and disease.

COPPER

Overview

Copper is required for cellular respiration,iron oxidation, pigment formation, neuro-transmitter biosynthesis, antioxidant defense,peptide amidation, and connective tissue for-mation (Pena et al. 1999). This metal is es-sential for central nervous system develop-ment, and disruption of copper homeostasisduring fetal life leads to perinatal mortality,severe growth retardation, and neurodegener-ation (Keen et al. 1998). Experiments in micereveal that the developmental timing of peri-natal copper deficiency influences the severityof neurological outcome, suggesting a criticalperiod for brain copper acquisition (Prohaska

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Table 1 The hereditary disorders of copper metabolism

Wilson disease Menkes diseaseGenetics Autosomal recessive X-linked

Loss-of-function mutations Loss-of-function mutations

Atp7b gene Atp7a genePresentation Late childhood: liver Early infancy

second–third decade, neuropsychiatricDefect Biliary copper excretion Copper transport across the placenta, brain, and gastrointestinal tractPathogenesis Copper accumulation Copper deficiencyClinical Cirrhosis, dystonia, dysarthria

Parkinsonian tremor, psychiatricHypothermia, hypopigmentation, abnormal hair, tortuous arteriesintractable seizures, failure to thrive

Pathology Basal ganglia copper accumulation Cerebral and cerebellar degenerationNeuronal cell loss Purkinje cell axonal swelling

Abnormal arborization

& Brokate 2002). Acquired copper deficiencyin adults results in myelopathy with lowerlimb spasticity and sensory ataxia due to as-cending sensory tract dysfunction and neu-rodegeneration of the dorsal column (Kumaret al. 2004, Prodan et al. 2006).

Menkes disease and Wilson disease arethe known inherited disorders of coppermetabolism in humans (Table 1). The essen-tial role of copper in the developing centralnervous system is evidenced by Menkes dis-ease, during which impaired copper transportinto and within the developing brain results indemyelination and neurodegeneration (Kaler1998, Kodama et al. 1999). Brain copper accu-mulation in Wilson disease results in dystonia,dysarthria, and other Parkinsonian symptoms,as well as psychiatric symptoms of depression,cognitive deterioration, personality change,psychosis, and schizophrenia (Ferenci 2004,Oder et al. 1991). Although the signs andsymptoms of Menkes and Wilson diseases aredistinct, each disorder results from inheritedloss-of-function mutations in genes encod-ing homologous copper-transporting P-typeadenosine triphosphatases (Atpases) Atp7aand Atp7b (Figure 1) (Culotta & Gitlin 2001).

Copper Metabolism

Copper is readily available in the diet and, fol-lowing absorption through the stomach and

duodenum, is rapidly removed from the por-tal circulation by hepatocytes in the liver. Bil-iary excretion is the only physiological mecha-nism of copper elimination, and at steady statethe amount of copper excreted into the bile isequivalent to that absorbed from the intestine(Gitlin 2003). The rate of copper excretioninto the bile increases promptly in responseto an increase in dietary copper, and excess ofthis metal does not occur in the absence of anunderlying metabolic defect (Gollan & Deller1973). This aspect of copper homeostasis iscritical to the interpretation of any study thatimplicates increases in dietary copper contentwith neurologic disease (Sparks & Schreurs2003).

Ctr1 is a plasma membrane protein essen-tial for early embryonic development and in-testinal copper uptake (Kuo et al. 2001, Leeet al. 2001, Nose et al. 2006) (Figure 2). Ctr1is present on endothelial cells of the blood-brain barrier, and expression at this site in-creases following perinatal copper deficiency(Kuo et al. 2006). These observations suggestthat copper is transported from the plasmainto the brain via Ctr1. Intracellular coppermetabolism is dependent on the copper trans-port Atpases, Atp7a and Atp7b. One of theseAtpases resides in the late Golgi of everycell, delivering copper to the secretory path-way for incorporation into cuproenzymes andexcretion (Figure 1). In the brain, Atp7a is

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expressed in endothelial cells of the blood-brain barrier and facilitates copper movementacross the basolateral membrane into the ex-travascular space of the brain. Atp7a is also ex-

Figure 1The copper-transporting P-type Atpases. a: Proposed structure of theAtpase homologues Atp7a and Atp7b. Motifs highlighted are theMXCXXC copper-binding motifs in the amino terminus, the DKTGTsequence that is the canonical phosphorylation site, the GDGVND Atpbinding domain and the conserved SEHPL, which contains the mostcommon mutation (H1069Q) in Wilson disease. Modified from Schaefer& Gitlin (1999) b. Merged image of Atp7a (red ) and late Golgi residentsyntaxin 6 (green) in a Nomarski differential interference contrast imageof a developing hippocampal neuron. Arrowheads reveal substantialoverlap of Atp7a in Golgi, whereas the arrow indicates Atp7a in processes.Scale bar 25 μM. Modified from Schlief et al. (2006).

pressed within specific populations of neuronsin several brain regions including the cere-bellum and hippocampus (Figure 3). Atp7bis expressed in hepatocytes and is requiredfor copper excretion from these cells into thebile. Copper-dependent trafficking of theseAtpases serves as the primary mechanismdetermining intracellular copper homeo-stasis (Lutsenko & Petris 2003, Petris et al.1996) (Figure 2).

Intracellular trafficking of copper also re-quires proteins termed metallochaperonesthat direct this metal to specific cellu-lar pathways (O’Halloran & Culotta 2000,Rae et al. 1999). These chaperones includeAtox1, which delivers copper to the copper-transporting Atpases in the late Golgi (Hamzaet al. 2001, 2003), CCS, which is requiredfor copper incorporation into cytoplasmicCu/Zn superoxide dismutase (Culotta et al.2006; Wong et al. 2000), and Cox17, Sco1,and Sco2, which deliver copper to mito-chondrial cytochrome c oxidase (Hamza &Gitlin 2002) (Figure 2). Sco1 and Sco2 alsofunction in a pathway of mitochondrial cop-per homeostasis (Leary et al. 2007). Metallo-thionein is a cysteine-rich cytoplasmic proteinthat chelates copper and is essential to protectagainst the toxicity caused by excess copper(Kelly & Palmiter 1996).

Copper is distributed throughout most re-gions of the brain and is most abundant in thebasal ganglia. Studies have detected this metalin the cell bodies of cortical pyramidal andcerebellar granular neurons, in the neuropil ofthe cerebral cortex, in the hippocampus andcerebellum, and in synaptic membranes of af-ferent nerves (Kozma et al. 1981, Sato et al.1994, Trombley & Shepherd 1996). In someneurons, copper is released at the synapse(Brown et al. 1997, Hartter & Barnea 1988)reaching micromolar concentrations (Kardoset al. 1989) that can abrogate long-term po-tentiation in the hippocampus (Doreulee et al.1997). Copper is an antagonist at N-methyl-D-aspartate (NMDA) receptors in cul-tured hippocampal neurons (Vlachova et al.1996, Weiser & Wienrich 1996), modulating


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Cox

Sco1Sco2

Cox 17

Atox1

CCS

Metallothionein

Cu / ZnSOD

Atp7aAtp7b

TGN

ApoproteinER

Mitochondrion Golgi

Cu

Ctr1

Cu excretionHolocuproprotein

Figure 2Cellular copper homeostasis. Model of copper trafficking in polarized cell reveals copper entry via Ctr1followed by distribution to the copper chaperones. The copper chaperone for superoxide dismutase(CCS) delivers copper to Cu/Zn superoxide dismutase (SOD1), Atox1 delivers copper to one of theAtpases (Atp7a/Atp7b) in the late Golgi and Cox17, and Sco1 and Sco2 are involved in the pathway ofcopper trafficking to mitochondria and cytochrome oxidase (Cox). The Atpases transport copper into thesecretory pathway for incorporation into newly synthesized cuproproteins and for export from the cell.Metallothionein serves to chelate most available copper and is critical for cell survival in copper excess.

Figure 3Atp7A expression and NMDA receptor–mediated trafficking. a: NeuroTrace staining of neuronsrevealing the overall architecture of the mouse hippocampus. Scale bar 150 μm. b: Boxed area in aenlarged as merged image of Atp7a (red ) and NeuroTrace reveals Atp7a expression in perinuclearneuronal compartment. c: Hippocampal neurons treated for 24 h with a 200-μM concentration of thecopper chelator BCS and immunolabeled for PSD-95 (green) and Atp7a (red ). d: Hippocampal neuronstreated for 24 h with a 200-μM concentration of the copper chelator BCS and 50 μM glutamate, 5 μMglycine, and immunolabeled for PSD-95 (green) and Atp7a (red ). Upon activation of NMDA receptors,Atp7a traffics from cell bodies down axonal processes localizing in part with postsynaptic densities (PSD).Arrows indicate regions of Atp7a overlap; arrowheads indicate regions distinct from PSD. Modified fromSchlief et al. (2005).


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activation of calcium-dependent cascades thatcontribute to synaptic plasticity (Lu et al.2001). Synaptic NMDA receptor activationresults in rapid and reversible trafficking ofAtp7a in cultured hippocampal neurons inassociation with copper release, suggestingthe presence of a mechanism linking copperhomeostasis and neuronal activation withinthe brain (Schlief et al. 2005) (Figure 3).

Menkes Disease

Menkes disease is an X-linked disorder char-acterized by growth failure, brittle hair, hy-popigmentation, arterial tortuosity, and neu-ronal degeneration due to loss-of-functionmutations in the gene encoding Atp7a (Chellyet al. 1993, Mercer et al. 1993, Vulpe et al.

1993). The pleiotropic features of this dis-ease are the result of impaired activity of spe-cific cuproenzymes resulting from impairedAtp7a function (Figure 2). The neurologicfeatures are present in early infancy, revealinga critical role for Atp7a and copper in neu-ronal development (Mercer 1998). Magneticresonance imaging of the brain reveals defi-cient myelination with cerebellar and cere-bral atrophy (Geller et al. 1997, Leventeret al. 1997), and neuropathologic examina-tion demonstrates focal degeneration of thegray matter and neuronal loss most prominentin the hippocampus and cerebellum (Barnardet al. 1978, Okeda et al. 1991) (Figure 4).

Although several of the known cuproen-zymes play critical roles in brain biochem-istry, the mechanisms of neurodegeneration

Figure 4Pathology in copper and iron disorders of the brain. a: Section of cerebellum from Menkes patient brainreveals abnormal Purkinje cell with axonal swelling and arborization (courtesy of K. Roth). b: Copperaccumulation in Wilson disease visible as Kayser-Fleischer rings in Descemet’s membrane at the limbusof the cornea (Gitlin 2003). c: Coronal brain section in aceruloplasminemia reveals cavitary degenerationand discoloration of basal ganglia (arrowheads). d: Prussian blue stain of putamen in aceruloplasminemiareveals iron accumulation in astrocytes and neurons (arrowheads) with neuronal loss (arrows) (Morita et al.1995).


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Table 2 The cuproenzymes

Enzyme Function Consequences of lossTyrosinase Melanin formation AlbinismLysyl oxidase1 Collagen and elastin cross link

formationPerinatal death: arterial aneurysms, diaphragmatic rupture(Hornstra et al. 2003)

Peptidylglycine α-amidatingmono-oxygenase

Activation of peptides with α

terminal glycineEmbryonic lethality: cardiac failure (normal CNS) (Czyzyket al. 2005)

Cu/Zn superoxide dismutase Antioxidant defense (superoxidedismutation)

Impaired pulmonary defenses to paraquat; infertility (Hoet al. 1998)

Ceruloplasmin Ferroxidase Parenchymal iron overload, anemia diabetes,neurodegeneration

Hephaestin Ferroxidase Impaired iron absorption, anemia (Vulpe et al. 1999)Dopamine β hydoxylase Norepinephrine synthesis Impaired sympathetic regulation, hypotension, hypoglycemiaCytochrome c oxidase Oxidative phosphorylation Encephalopathy, muscle weakness, cardiac failure—neonate

1Consists of family of five known genes in humans; copper dependence and function of other members are not yet clearly elucidated.

in Menkes disease are unknown and not ex-plained by impaired activity of any of theseenzymes (Table 2). Studies in a murine modelof Menkes disease suggest a role for Atp7aand copper in axon extension and synaptoge-nesis during development (El Meskini et al.2005). Atp7a mediates the availability of anNMDA receptor–dependent, releasable poolof copper in hippocampal neurons (Schliefet al. 2005), and the absence of Atp7a ac-tivity in Menkes disease markedly accentu-ates NMDA receptor–mediated excitotoxicityin these neurons (Schlief et al. 2006). Thesedata suggest a model whereby loss of Atp7acontributes to both seizures and neuronal de-generation in affected patients and raise thepossibility of therapeutic approaches based onNMDA receptor blockade (Hardingham &Bading 2003, Schlief & Gitlin 2006).

Systemic copper treatment is not effec-tive in patients with Menkes disease be-cause copper transport into the brain is de-pendent on Atp7a. Rare patients with someresidual Atp7a activity have less central ner-vous system pathology despite significant sys-temic disease (Moller et al. 2000) and whentreated with copper evidence neurodevelop-mental improvement (Christodoulou et al.1998, Kaler et al. 1995). This clinical observa-tion reveals a hierarchy of copper distributionpreferential to the brain under circumstances

of limited copper availability, a concept sup-ported by recent observations in a zebrafishmodel of Menkes disease (Mendelsohn et al.2006). The mechanisms of this hierarchy areunclear but this process illustrates copper’s es-sential role in brain development.

Wilson Disease

Wilson disease is an autosomal recessive dis-order resulting in hepatic cirrhosis and pro-gressive basal ganglia degeneration due toloss-of-function mutations in the gene encod-ing the copper-transporter Atp7b (Bull et al.1993, Tanzi et al. 1993, Yamaguchi et al.1993). The resulting impairment in biliarycopper excretion leads to hepatocyte copperaccumulation, copper-mediated liver damage,activation of cell-death pathways, leakage ofcopper into the plasma, and eventual copperoverload in all tissues (Figure 4) (Gitlin 2003,Tao 2003). Although Atp7b is expressed insome regions of the brain, in Wilson diseasecopper overload in extrahepatic tissues is dueto excess accumulation from the plasma fol-lowing liver injury because this is entirely re-versed following liver transplantation (Emreet al. 2001, Schumacher et al. 2001).

Ceruloplasmin is an essential ferroxidasethat contains greater than 95% of the copperpresent in plasma. This protein is synthesized


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Apoceruloplasmin

Atox1

Atp7b

Bile

Metallothionein

Ctr1

Ceruloplasmin

Ctr1

Mitochondrialdamage

Cellular Injury

Hepatocytes

Normal Wilson disease

TGNTGN

ER

ER

Mitochondrion

Figure 5Pathogenesis ofWilson disease.Model of theproposed pathwaysand proteinsrelevant to coppermetabolism in thehuman hepatocyte.Copper transportto the trans-Golginetwork (TGN) isshown as theprocess mediatingintracellularhomeostasis byAtp7b.Dysfunction resultsin cytosolic copperaccumulation withassociated cellulardamage.

in hepatocytes and secreted into the plasmafollowing the incorporation of six copperatoms in the late secretory pathway. In Wilsondisease, loss of function of Atp7b results insynthesis of apoceruloplasmin that is rapidlydegraded in the plasma (Figure 5). As a re-sult, the serum ceruloplasmin concentrationis a useful diagnostic indicator of Wilson dis-ease (Hellman & Gitlin 2002).

Almost half of all patients with Wilson dis-ease present with signs and symptoms of neu-ropsychiatric illness (Gollan & Gollan 1998).Although such neurological features may ini-tially be subtle, without chelation patientswill progress to severe Parkinsonian symp-toms, consistent with the neuropathologicfindings of basal ganglia copper accumulationand neurodegeneration (Oder et al. 1991).Neurodegeneration in Wilson disease resultsdirectly from copper accumulation, but theprecise mechanisms of cellular injury are un-known. Psychiatric symptoms are also com-mon and range from behavioral problems topsychosis (Dening 1991). These abnormali-ties, although without neuropathologic cor-relates, are clearly the result of brain copper

accumulation because prompt improvementis observed upon treatment with oral chelat-ing agents to restore copper homeostasis. Thereversible nature of many of these psychi-atric symptoms is consistent with the conceptthat copper can modulate synaptic function(Schlief & Gitlin 2006) and suggests novel av-enues for investigation in common psychiatricdisorders.

IRON

Overview

Iron is required as a cofactor in central ner-vous system metabolic processes includingoxidative phosphorylation, neurotransmitterproduction, nitric oxide metabolism, and oxy-gen transport (Ponka 1999). The observationthat brain iron content is increased in patientswith Parkinson disease and other neurode-generative disorders has created significantinterest in the possibility that disturbancesof brain iron homeostasis may contribute tothe pathogenesis of these diseases (Thomas& Jankovic 2004). Although numerous


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clinical and experimental studies have at-tempted to address this issue, a causative rolefor impaired iron homeostasis has yet to be es-tablished in these more common neurodegen-erative diseases. Nevertheless, interest in thisneuropathology has focused increased atten-tion on elucidating the mechanisms of brainiron homeostasis and on defining iron’s rolein neurologic disease.

The inherited diseases of iron metabolismare more common and more numerous thanthose of copper, and the genetic basis of manyof these disorders has been characterized(Andrews 2002). Although many of the pro-teins shown to be essential for systemic ironhomeostasis are expressed within the brain(Wu et al. 2004, Zecca et al. 2004), geneticdisorders resulting in loss of function of theseproteins rarely result in either brain iron over-load or deficiency or neurologic disease. Forexample, although ferroportin is abundantlyexpressed in the brain microvasculature and isthe only known cellular iron exporter, patientswith mutations that impair this protein’s func-tion have no evidence of brain iron accumula-tion (Pietrangelo 2006b). These observations

suggest the presence of unique mechanismsregulating iron metabolism within the centralnervous system.

Iron Metabolism

Genetic analysis of the inherited ironmetabolism disorders has identified manyof the proteins necessary for systemic ironhomeostasis (Hentze et al. 2004, Pietrangelo2006a) (Figure 6). Ferrous iron (Fe2+) istaken up into cells by the divalent membranetransporter DMT1, whereas ferric iron (Fe3+)enters cells via endocytosis of the transfer-rin receptor following binding to transferrin(Andrews & Schmidt 2006). The most com-pelling feature of systemic iron homeostasisis that iron requirements far exceed the gas-trointestinal absorption capacity, and thus al-most all the iron utilized each day is continu-ously recycled from internal stores (Koury &Ponka 2004) (Figure 7). Central to this pro-cess is the hepatocyte-derived peptide hep-cidin, which regulates iron availability inresponse to hypoxia, inflammation, erythro-poietic needs, and iron stores (Nemeth &

Fe 2+

Transferrin

Transferrinreceptor

DMT1

Steap3

FerritinL

HFerroportin

CeruloplasminCu

Fe2+

Mitoferrin

FrataxinS

SL

H

Heme

Fe3+

Fe3+

Hepcidin

Figure 6Pathways of cellular iron homeostasis. Iron uptake can occur via the transferrin receptor and the divalenttransporter DMT1. Steap3 is a ferrireductase critical for transferrin-mediated iron release into the cell.Ferritin is the predominant storage protein consisting of heavy chains with ferroxidase activity and lightchains. Ferroportin is the only known cellular iron exporter, and ceruloplasmin is a ferroxidase mediatingefficient cellular iron release. Iron homeostasis is regulated by hepcidin, a circulating peptide that binds toferroportin, mediating uptake and degradation of this exporter. Iron enters mitochondria via mitoferrin,and frataxin is a mitochondrial protein mediating Fe-S cluster formation and heme biosynthesis.


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aLiver

Bonemarrow

Erythrocytes

Iron cycle

Spleen

Erythropoiesis

Ferroportin

Reticuloendothelialcells

CeruloplasminTransferrin

Transferrin receptor

Neuron

b

Brain ironcycle

Ceruloplasmin

Neuron

Transferrin

Blood-brain

barrier Aceruloplasminemia

Ferritin

Glia

DMT1

Glia

Neuroferritinopathy

Fe 2+

Fe 2+

Fe 3+

Fe 3+

Figure 7Iron cycles and the pathogenesis of brain iron disease. a: Systemic iron cycle allows for rapid utilizationof iron and is dependent on ceruloplasmin to establish a rate of iron oxidation sufficient for mobilizationfrom reticuloendothelium. b: Iron crosses the blood brain barrier via transferrin receptor pathway onendothelium. The brain iron cycle consists of glia and neurons, where gpi-linked ceruloplasmin functionsin a similar role as in the periphery. In aceruloplasminemia, excess iron accumulation damages glia, andneurons are subsequently injured from loss of glia-derived factors, iron-deficiency, or accumulation ofnontransferrin-bound iron. A similar pathogenesis is proposed for neuroferritinopathy.

Ganz 2006). Hepcidin binds to and inducesthe endocytosis and turnover of the plasmamembrane iron exporter ferroportin, whichis the primary determinant of gastrointestinaliron absorption and iron release from retic-uloendothelial stores (Nemeth et al. 2004).Ceruloplasmin plays a critical role in this pro-

cess by establishing a rate of plasma iron ox-idation sufficient for the continued release ofthis metal from the storage sites (Harris et al.1998) (Figure 7).

Iron is taken up into the brain from theplasma via transferrin receptor–mediated en-docytosis in the brain capillaries and returned


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to circulation via absorption of cerebrospinalfluid (Moos et al. 2006). Brain iron accountsfor less than 2% of the total body iron contentand varies greatly in amount and concentra-tion depending on the specific region of thebrain. The concentration of iron in the brain isgreatest in the basal ganglia where it is equiva-lent to that found in the liver, suggesting a rolein brain iron storage and distribution (Haackeet al. 2005). Iron is widely distributed in all celltypes within the central nervous system but isabundant especially in astrocytes, supportingthe idea that these cells and other types of gliafunction in iron storage and regulation.

Iron requirements in the brain are muchgreater than the observed rate of iron uptakeinto this tissue (Bradbury 1997). This find-ing suggests most brain iron used each dayis derived from recycling behind the blood-brain barrier analogous to what occurs inthe periphery (Figure 7). This mechanismwould protect the brain from the effects ofsystemic iron overload or deficiency and issupported by observations that disturbancesof systemic iron homeostasis exhibit minimaleffects on central nervous system iron contentor metabolism (Moos & Morgan 2004). Therate of brain iron uptake is greatest duringfetal life and postnatal iron repletion is inef-fective to correct the cognitive defects aris-ing from iron deficiency in utero; this con-cept indicates that following birth recycling,

rather than uptake from the circulation, is themajor iron source for brain function (Lozoffet al. 2006). Existence of this brain iron cyclehas critical implications for interpreting anyfinding of brain iron accumulation in disease.The inherited disorders aceruloplasminemiaand neuroferritinopathy support the conceptof a brain iron cycle and demonstrate that dys-regulation of brain iron homeostasis can be aprimary cause of neurodegeneration (Ponka2004) (Table 3).

Aceruloplasminemia

Aceruloplasminemia is an autosomal reces-sive disorder of iron homeostasis caused byloss-of-function mutations in the ceruloplas-min gene (Harris et al. 1995, Yoshida et al.1995). Patients have absent serum ceruloplas-min, decreased serum iron, elevated serumferritin, anemia, and insulin-dependent dia-betes mellitus (Gitlin 1998, Nittis & Gitlin2002). Despite these systemic features, mostpatients present with progressive dementia,dysarthria, and dystonia secondary to basalganglia iron accumulation (Logan et al. 1994,Miyajima et al. 1987, Morita et al. 1995). Theneurologic disease in aceruloplasminemia isalways associated with increased brain ironas detected by magnetic resonance imagingor autopsy (Kono & Miyajima 2006). Histo-logical findings from affected brain regions

Table 3 The hereditary disorders of brain iron metabolism

Aceruloplasminemia NeuroferritinopathyGenetics Autosomal recessive loss-of-function mutations

ceruloplasmin geneAutosomal dominant (dominant-negative) mutationsferritin light chain gene

Presentation Third decade—diabetes Third through sixth decadeFifth decade—neurologic

Defect Brain iron recycling Brain iron storagePathogenesis Brain iron accumulation Brain iron accumulation

Systemic iron accumulationClinical Diabetes, anemia, dementia Dementia, dystonia, dysarthria

Dystonia, dysarthriaPathology Iron accumulation in astrocytes Iron accumulation in astrocytes

Neuronal loss Neuronal loss


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include neuronal cell loss, abnormal astrocytearchitecture, and excess iron deposition in gliaand neurons (Kaneko et al. 2002, Morita et al.1995, Oide et al. 2006) (Figure 4).

The absence of ceruloplasmin results inthe slow accumulation of iron in the retic-uloendothelial cells where this metal is nor-mally stored and then mobilized for recy-cling (Harris et al. 1999, Patel et al. 2002)(Figure 7). This mechanism of systemic ironaccumulation also occurs in patients withdominant-negative mutations in the gene en-coding the iron exporter ferroportin (DeDomenico et al. 2006). Loss of ceruloplas-min also results in increased nontransferrin-bound iron that rapidly accumulates in theliver, pancreas, and other tissues following re-moval from the plasma by DMT1 (Andrews2002, Hentze et al. 2004) (Figure 7). Thismechanism of tissue iron accumulation alsooccurs in atransferrinemia, where the ab-sence of serum transferrin increases the rela-tive amount of nontransferrin-bound plasmairon (Craven et al. 1987); in HFE hemochro-matosis, where excess iron absorption elevatesnontransferrin-bound plasma iron (Andrews2002); in the thalassemias and other forms ofsecondary iron overload, where transfusion-dependency elevates nontransferrin-boundplasma iron (Pietrangelo 2006b); and inhemochromatosis, owing to loss-of-functionmutations in ferroportin that impair hep-cidin regulation inappropriately increasingnontransferrin-bound iron (De Domenicoet al. 2006).

Although these disorders of iron meta-bolism share common mechanisms of tis-sue iron overload, accumulation of iron inthe brain is unique to aceruloplasminemia.The absence of brain iron accumulation inother diseases with increased nontransferrin-bound plasma iron supports the idea thatbrain iron accumulation in aceruloplasmine-mia results directly from impaired iron home-ostasis within the central nervous system.Consistent with this concept, ceruloplas-min is synthesized in astrocytes (Klompet al. 1996, Klomp & Gitlin 1996) as

a glycophosphatidylinositol-linked isoform(Jeong & David 2003, Patel et al. 2000), sug-gesting that this membrane-bound ferroxi-dase facilitates the rate of iron release fromstorage cells within the central nervous sys-tem. Ceruloplasmin is one of very few pro-teins established as playing a critical role inbrain iron homeostasis.

Neuroferritinopathy

Ferritin is a ubiquitously expressed cytoplas-mic iron storage protein consisting of heavyand light chains encoded on separate genes(Figure 6). Iron-dependent translational reg-ulation of this protein by the cytosolic ironregulatory proteins Irp1 and Irp2 ensures thatferritin is a readily available source of intra-cellular iron in all cells including neuronsand glia (Rouault 2006). Neuroferritinopa-thy, an autosomal dominant extrapyramidaldisease resulting from mutations in the geneencoding the light chain of ferritin, has re-vealed a primary role for ferritin in brainiron homeostasis (Curtis et al. 2001, Macielet al. 2005, Mancuso et al. 2005, Vidal et al.2004). Pathological examination of affectedpatients reveals cavitary degeneration in thebasal ganglia nuclei, neuronal loss, and ironand ferritin in both extracellular and cytoplas-mic inclusion bodies of microglia. The au-tosomal dominant inheritance and the mul-timeric structure of ferritin suggest that thesemutations impair ferritin assembly resultingin loss of iron storage capacity within braincells and subsequent iron-mediated cell injury(Levi et al. 2005). Although there are somephenotype-genotype correlations specific toeach light chain mutation, all patients withneuroferritinopathy evidence dystonia in as-sociation with basal ganglia iron accumulation(Chinnery et al. 2007).

Patients with neuroferritinopathy expressthe ferritin light chain mutation in all cellsyet evidence no abnormalities in systemic ironhomeostasis with the exception of decreasedserum ferritin (Chinnery et al. 2007). Thisfinding suggests either a unique role for the


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ferritin light chain in some cell types withinthe brain or a greater sensitivity of thesecells to this form of iron-dependent injury.Although the mechanism of neurodegenera-tion in neuroferritinopathy is unknown, thesimilar pathology to aceruloplasminemia sug-gests a role for ferritin in the brain iron cy-cle and implies a common iron-dependentmechanism of neurodegeneration in these twodiseases (Figure 7). Recent studies in aceru-loplasminemia suggest that neuronal loss inthis disease arises from iron deficiency sec-ondary to impaired iron movement from as-trocytes within the brain iron cycle ( Jeong &David 2006). Support for a similar mechanismin neuroferritinopathy comes from a murinemodel of Irp2 deficiency that impairs fer-ritin regulation, results in iron accumulationwithin oligodendrocytes, and leads to neu-rodegeneration most likely from secondaryneuronal iron deficiency (LaVaute et al.2001).

Friedreich’s Ataxia

Friedreich’s ataxia is an autosomal recessivedisorder characterized by sensory neuron,cerebellar, and cardiomyocyte degeneration(Durr et al. 1996) due to loss of function offrataxin, a mitochondrial protein involved ininorganic iron-sulfur (Fe/S) cluster biogenesis(Babcock et al. 1997). Although not specific tothe brain, the effect of impaired mitochondrialiron homeostasis on neuronal survival in thisdisease warrants mention here. Mitochondrialiron is required for heme biosynthesis andfor the generation of Fe/S clusters that areprosthetic groups in many essential enzymes(Ajioka et al. 2006, Lill & Muhlenhoff 2006).Iron is imported into mitochondria by mito-ferrin, a transporter expressed in the innermitochondrial membrane (Shaw et al. 2006),and exits mitochondria largely in the formof Fe/S clusters (Rouault & Tong 2005). Al-though excess mitochondrial iron is detectedin cardiomyocytes and sensory neurons fromaffected patients (Puccio et al. 2001), impair-ment of heme and Fe/S cluster biosynthesis is

the likely proximate cause of neurodegenera-tion in Friedreich’s ataxia (Lill & Muhlenhoff2006, Voncken et al. 2004).

Neurodegeneration with Brain IronAccumulation

Neurodegeneration with brain iron accumu-lation describes a heterogeneous group ofpatients with progressive neurodegenerationand iron deposition in the basal ganglia(Gregory & Hayflick 2005, Hayflick et al.2003). Most of these patients present inchildhood with dystonia, dysarthria, andpigmentary retinopathy and have autosomalrecessive, loss-of-function mutations in thegene-encoding mitochondrial pantothenatekinase 2, an essential mitochondrial en-zyme involved in coenzyme A biosynthesis(Hayflick et al. 2003, Johnson et al. 2004,Zhou et al. 2001). The mechanisms of iron ac-cumulation and the role of iron, if any, in thepathogenesis are unknown. However, thesedisorders deserve mention because recentstudies reveal mutations in the gene encodinga calcium-independent group VI phospholi-pase A2 in some children with brain iron accu-mulation and neurodegeneration, suggestinga novel link between phospholipid and ironmetabolism in the brain (Morgan et al. 2006).

CONCLUSIONS

The inherited disorders of copper metabolismreveal copper’s essential role in brain devel-opment and neuropsychiatric disease. Themechanisms of psychiatric disease observed inpatients with Wilson disease are of particu-lar interest. Chelation is an effective therapyin such individuals, indicating copper’s directrole in pathogenesis and suggesting avenuesfor study that may be widely applicable tobrain function and mental health. Althoughelucidation of the genetic basis of Menkesand Wilson diseases has revealed much aboutthe cell biology of copper metabolism, muchmore needs to be learned about the nor-mal mechanisms of copper homeostasis in


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the brain. In particular, the role of the basalganglia in copper and iron storage and distri-bution needs further study as do the mech-anisms of this brain region’s vulnerability toexcess copper and iron. Recent studies havefocused on copper’s role in the pathogen-esis of prion-mediated encephalopathy andAlzheimer disease, including the proposedtreatment of affected patients with metalchelating drugs (Bush 2000, Doraiswamy& Finefrock 2004, Gaeta & Hider 2005).However, caution is warranted because moreknowledge of copper homeostasis within thebrain and copper’s role in specific neurologicfunctions is required before any such thera-peutic approaches can be thoughtfully under-taken or interpreted.

The discovery of aceruloplasminemia andneuroferritinopathy demonstrates that dys-regulation of brain iron homeostasis can bea primary cause of neurodegeneration. Theseinherited disorders provide a platform for fur-ther mechanistic investigations that should re-veal new insights into brain iron homeostasis.Nevertheless, absent further understanding ofthe molecular mechanisms of iron homeosta-sis in the central nervous system, investigators

currently cannot interpret the significanceof iron accumulation in the pathogenesis ofother neurologic diseases (Lee et al. 2006,Zecca et al. 2004). This concept is illustratedby recent studies in aceruloplasminemia thatsuggest that neurodegeneration arises fromiron deficiency despite the marked brain ironoverload. A cautionary tale is also provided bythe numerous iron chelator and antioxidanttrials initiated in patients with Friedreich’sataxia on the basis of the findings of mitochon-drial iron accumulation, none of which haveany demonstrated clinical benefit in double-blind placebo-controlled trials. These data re-mind us of the need for critical, mechanisticapproaches to defining disease pathogenesiswhen normal physiology remains poorly un-derstood. In this regard, attention is given torecent studies identifying a signaling cascadein neurons where stimulation of NMDA re-ceptors mediates iron uptake via the divalentiron transporter DMT-1. This work providesa physiologic link between neuronal functionand iron homeostasis and suggests mecha-nisms linking iron and NMDA neurotoxicitythat would direct future investigation (Cheahet al. 2006).

ACKNOWLEDGMENTS

The study of copper and iron disorders of the brain in J.G.’s laboratory is supported by theNational Institutes of Health (DK44464, DK61763, HD39952). E.M. was supported by NIHMedical Scientist Training Program grant T32 GM07200.

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Annual Review ofNeuroscience

Volume 30, 2007Contents

Information Processing in the Primate Retina: Circuitry and CodingG.D. Field and E.J. Chichilnisky � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �1

Orbitofrontal Cortex and Its Contribution to Decision-MakingJonathan D. Wallis � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 31

Fundamental Components of AttentionEric I. Knudsen � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 57

Anatomical and Physiological Plasticity of Dendritic SpinesVeronica A. Alvarez and Bernardo L. Sabatini � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 79

Visual Perception and Memory: A New View of Medial TemporalLobe Function in Primates and RodentsElisabeth A. Murray, Timothy J. Bussey, and Lisa M. Saksida � � � � � � � � � � � � � � � � � � � � � � � � 99

The Medial Temporal Lobe and Recognition MemoryH. Eichenbaum, A.P. Yonelinas, and C. Ranganath � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �123

Why Is Wallerian Degeneration in the CNS So Slow?Mauricio E. Vargas and Ben A. Barres � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �153

The Head Direction Signal: Origins and Sensory-Motor IntegrationJeffrey S. Taube � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �181

Peripheral RegenerationZu-Lin Chen, Wei-Ming Yu, and Sidney Strickland � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �209

Neuron-Glial Interactions in Blood-Brain Barrier FormationSwati Banerjee and Manzoor A. Bhat � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �235

Multiple Dopamine Functions at Different Time CoursesWolfram Schultz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �259

Ventral Tegmental Area Neurons in Learned Appetitive Behavior andPositive ReinforcementHoward L. Fields, Gregory O. Hjelmstad, Elyssa B. Margolis,

and Saleem M. Nicola � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �289

v

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AR314-FM ARI 20 May 2007 16:26

Copper and Iron Disorders of the BrainErik Madsen and Jonathan D. Gitlin � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �317

The Micromachinery of Mechanotransduction in Hair CellsMelissa A. Vollrath, Kelvin Y. Kwan, and David P. Corey � � � � � � � � � � � � � � � � � � � � � � � � � � � � �339

Neurobiology of Feeding and Energy ExpenditureQian Gao and Tamas L. Horvath � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �367

Mechanisms that Regulate Establishment, Maintenance, andRemodeling of Dendritic FieldsJay Z. Parrish, Kazuo Emoto, Michael D. Kim, and Yuh Nung Jan � � � � � � � � � � � � � � � � �399

Dynamic Aspects of CNS Synapse FormationA. Kimberley McAllister � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �425

Adhesion Molecules in the Nervous System: Structural Insights intoFunction and DiversityLawrence Shapiro, James Love, and David R. Colman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �451

Development of Neural Systems for ReadingBradley L. Schlaggar and Bruce D. McCandliss � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �475

Molecular Architecture of Smell and Taste in DrosophilaLeslie B. Vosshall and Reinhard F. Stocker � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �505

The Neural Basis of Decision MakingJoshua I. Gold and Michael N. Shadlen � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �535

Trinucleotide Repeat DisordersHarry T. Orr and Huda Y. Zoghbi � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �575

Indexes

Cumulative Index of Contributing Authors, Volumes 21–30 � � � � � � � � � � � � � � � � � � � � � � � �623

Cumulative Index of Chapter Titles, Volumes 21–30 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �627

Errata

An online log of corrections to Annual Review of Neuroscience chapters (if any, 1997to the present) may be found at http://neuro.annualreviews.org/

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