Copper and Iron Disorders of the Brain

Erik Madsen and Jonathan D. Gitlin
Annu. Rev. Neurosci. 2007.30:317-337. Downloaded from by University of California - Berkeley on 04/10/12. For personal use only.
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63130; email:,

Annu. Rev. Neurosci. 2007. 30:317–37 First published online as a Review in Advance on March 16, 2007 The Annual Review of Neuroscience is online at 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

Copper and iron are transition elements essential for life. These metals are required to maintain the brain’s biochemistry such that deficiency or excess of either copper or iron results in central nervous system disease. This review focuses on the inherited disorders in humans that directly affect copper or iron homeostasis in the brain. Elucidation of the molecular genetic basis of these rare disorders has provided insight into the mechanisms of copper and iron acquisition, trafficking, storage, and excretion in the brain. This knowledge permits a greater understanding of copper and iron roles in neurobiology and neurologic disease and may allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.


INTRODUCTION . . . . . . . . . . . . . . . . . COPPER . . . . . . . . . . . . . . . . . . . . . . . . . . . Overview . . . . . . . . . . . . . . . . . . . . . . . . Copper Metabolism . . . . . . . . . . . . . . Menkes Disease . . . . . . . . . . . . . . . . . . Wilson Disease . . . . . . . . . . . . . . . . . . . IRON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Overview . . . . . . . . . . . . . . . . . . . . . . . . Iron Metabolism . . . . . . . . . . . . . . . . . Aceruloplasminemia . . . . . . . . . . . . . . Neuroferritinopathy . . . . . . . . . . . . . . Friedreich’s Ataxia . . . . . . . . . . . . . . . . Neurodegeneration with Brain Iron Accumulation . . . . . . . . . . . . CONCLUSIONS . . . . . . . . . . . . . . . . . . . 318 318 318 319 322 323 324 324 325 327 328 329 329 329

Annu. Rev. Neurosci. 2007.30:317-337. Downloaded from by University of California - Berkeley on 04/10/12. For personal use only.

Copper and iron function as cofactors in specific proteins, catalyzing electron transfer reactions required for cellular metabolism and binding inorganic ions (e.g., oxygen) that serve as substrates for this biochemistry (Andrews & Schmidt 2006, Balamurugan & Schaffner 2006). Deficiency in these metals results in metabolic abnormalities due to loss of function of these iron- and copperdependent proteins. Excess of these metals can result in the unregulated oxidation of proteins, lipids, and other cellular components causing subsequent tissue injury. Thus pathways of copper and iron metabolism have evolved to ensure adequate amounts of each metal for cellular survival while protecting the organism from the consequences of metal excess. In the past decade, elucidation of the genetic basis of many of the inherited copper and iron metabolism disorders has begun to provide insight into these pathways, permitting an understanding of the mechanisms involved in cellular homeostasis of these metals. The inherited copper and iron metabolism disorders that cause deficiency or excess of these metals in the brain result in central nervous system disease (Ponka 2004, Waggoner
318 Madsen

et al. 1999). Although these disorders reveal that copper and iron homeostasis is essential for normal brain function, little is currently known about the mechanisms of copper and iron acquisition, trafficking, storage, and excretion within the central nervous system. How and where are iron and copper stored in the brain and under which circumstances do these metals accumulate? How do cells in the brain acquire these metals when needed? Why is iron deficiency in utero associated with significant long-term cognitive impairment? How are the uptake and excretion of these metals regulated in the brain, and what is the relationship to these processes in systemic circulation? How does excess copper accumulation within the brain result in psychiatric disease? Does impaired homeostasis of copper or iron contribute to the pathogenesis of common neurodegenerative disorders such as Parkinson or Alzheimer disease? One only has to view the clinical consequences of accumulation or deficiency of these metals in the human brain to appreciate the critical nature of such questions. Mechanistic understanding of the human genetic disorders that impair copper or iron homeostasis in the brain provides insight into the role of these metals in neurobiology and disease.

COPPER Overview
Copper is required for cellular respiration, iron oxidation, pigment formation, neurotransmitter biosynthesis, antioxidant defense, peptide amidation, and connective tissue formation (Pena et al. 1999). This metal is essential for central nervous system development, and disruption of copper homeostasis during fetal life leads to perinatal mortality, severe growth retardation, and neurodegeneration (Keen et al. 1998). Experiments in mice reveal that the developmental timing of perinatal copper deficiency influences the severity of neurological outcome, suggesting a critical period for brain copper acquisition (Prohaska



1991). Neurosci. Nose et by University of California . This aspect of copper homeostasis is critical to the interpretation of any study that implicates increases in dietary copper content with neurologic disease (Sparks & Schreurs 2003). and expression at this site increases following perinatal copper deficiency (Kuo et al. 2001. and excess of this metal does not occur in the absence of an underlying metabolic defect (Gollan & Deller 1973). Atp7a is www. dystonia. cognitive deterioration. These observations suggest that copper is transported from the plasma into the brain via Ctr1. Rev. The rate of copper excretion into the bile increases promptly in response to an increase in dietary copper. 2006). For personal use only. The essential role of copper in the developing central nervous system is evidenced by Menkes disease. Ctr1 is a plasma membrane protein essential for early embryonic development and intestinal copper uptake (Kuo et al. hypopigmentation.Berkeley on 04/10/12. Menkes disease and Wilson disease are the known inherited disorders of copper metabolism in humans (Table 1). 2001. Intracellular copper metabolism is dependent on the copper transport Atpases. 1999). Atp7a and Atp7b. delivering copper to the secretory pathway for incorporation into cuproenzymes and excretion (Figure 1). Kodama et al. is rapidly removed from the portal circulation by hepatocytes in the liver. & Brokate 2002). dysarthria. and schizophrenia (Ferenci 2004. 2004. Acquired copper deficiency in adults results in myelopathy with lower limb spasticity and sensory ataxia due to ascending sensory tract dysfunction and neurodegeneration of the dorsal column (Kumar et al. 2006) (Figure 2). each disorder results from inherited loss-of-function mutations in genes encoding homologous copper-transporting P-type adenosine triphosphatases (Atpases) Atp7a and Atp7b (Figure 1) (Culotta & Gitlin 2001).Table 1 Genetics The hereditary disorders of copper metabolism Wilson disease Autosomal recessive Loss-of-function mutations Atp7b gene X-linked Loss-of-function mutations Atp7a gene Early infancy Copper transport across the placenta. and other Parkinsonian symptoms. Brain copper accumulation in Wilson disease results in dystonia. neuropsychiatric Biliary copper excretion Copper accumulation Cirrhosis. failure to thrive Cerebral and cerebellar degeneration Purkinje cell axonal swelling Abnormal arborization Menkes disease Presentation Defect Pathogenesis Clinical Pathology Late childhood: liver second–third decade. Prodan et al. personality change. One of these Atpases resides in the late Golgi of every cell.30:317-337.annualreviews. tortuous arteries intractable • Copper and Iron in the Brain 319 . abnormal hair. Lee et al. psychiatric Basal ganglia copper accumulation Neuronal cell loss Annu. and gastrointestinal tract Copper deficiency Hypothermia. Copper Metabolism Copper is readily available in the diet and. as well as psychiatric symptoms of depression. Downloaded from www. 2006). following absorption through the stomach and duodenum. Ctr1 is present on endothelial cells of the bloodbrain barrier. dysarthria Parkinsonian tremor. psychosis. and at steady state the amount of copper excreted into the bile is equivalent to that absorbed from the intestine (Gitlin 2003). Biliary excretion is the only physiological mechanism of copper elimination. Oder et al. In the brain.annualreviews. 2007. during which impaired copper transport into and within the developing brain results in demyelination and neurodegeneration (Kaler 1998. brain. Although the signs and symptoms of Menkes and Wilson diseases are distinct.

in the neuropil of the cerebral cortex. 1997). Intracellular trafficking of copper also requires proteins termed metallochaperones that direct this metal to specific cellular pathways (O’Halloran & Culotta 2000. copper is released at the synapse (Brown et al. Weiser & Wienrich 1996). in the hippocampus and cerebellum. and Cox17.expressed in endothelial cells of the bloodbrain barrier and facilitates copper movement across the basolateral membrane into the extravascular space of the brain. 1994. Sato et al. Wong et al. Modified from Schlief et al. and Sco2. a: Proposed structure of the Atpase homologues Atp7a and Atp7b. 2007). 1996) (Figure 2). Atp7b is expressed in hepatocytes and is required for copper excretion from these cells into the bile. 2007. 1981. Hartter & Barnea 1988) reaching micromolar concentrations (Kardos et al.annualreviews. 1989) that can abrogate long-term potentiation in the hippocampus (Doreulee et al. 320 Madsen pressed within specific populations of neurons in several brain regions including the cerebellum and hippocampus (Figure 3). modulating Annu. the DKTGT sequence that is the canonical phosphorylation site. Arrowheads reveal substantial overlap of Atp7a in by University of California . and in synaptic membranes of afferent nerves (Kozma et al. Rev. which contains the most common mutation (H1069Q) in Wilson disease. 2000). For personal use only. Merged image of Atp7a (red ) and late Golgi resident syntaxin 6 (green) in a Nomarski differential interference contrast image of a developing hippocampal neuron. Trombley & Shepherd 1996). 2003). Sco1 and Sco2 also function in a pathway of mitochondrial copper homeostasis (Leary et al. Neurosci. (2006). which delivers copper to the coppertransporting Atpases in the late Golgi (Hamza et al. Petris et al.30:317-337. Copper-dependent trafficking of these Atpases serves as the primary mechanism determining intracellular copper homeostasis (Lutsenko & Petris 2003. 2001. These chaperones include Atox1. whereas the arrow indicates Atp7a in processes. Sco1. Copper is distributed throughout most regions of the brain and is most abundant in the basal ganglia. · Gitlin . Motifs highlighted are the MXCXXC copper-binding motifs in the amino terminus. Atp7a is also ex- Figure 1 The copper-transporting P-type Atpases. 2006. 1996. CCS. Rae et al. which deliver copper to mitochondrial cytochrome c oxidase (Hamza & Gitlin 2002) (Figure 2). Studies have detected this metal in the cell bodies of cortical pyramidal and cerebellar granular neurons.Berkeley on 04/10/12. 1997. In some neurons. Downloaded from www. Metallothionein is a cysteine-rich cytoplasmic protein that chelates copper and is essential to protect against the toxicity caused by excess copper (Kelly & Palmiter 1996). the GDGVND Atp binding domain and the conserved SEHPL. Copper is an antagonist at N-methylD-aspartate (NMDA) receptors in cultured hippocampal neurons (Vlachova et al. which is required for copper incorporation into cytoplasmic Cu/Zn superoxide dismutase (Culotta et al. 1999). Scale bar 25 μM. Modified from Schaefer & Gitlin (1999) b.

and immunolabeled for PSD-95 (green) and Atp7a (red ).annualreviews. and Sco1 and Sco2 are involved in the pathway of copper trafficking to mitochondria and cytochrome oxidase (Cox). The Atpases transport copper into the secretory pathway for incorporation into newly synthesized cuproproteins and for export from the cell.Cox Sco2 Sco1 Cox 17 Mitochondrion Cu Atox1 Ctr1 CCS Metallothionein Atp7a Atp7b Apoprotein ER TGN Golgi Annu. a: NeuroTrace staining of neurons revealing the overall architecture of the mouse hippocampus. Metallothionein serves to chelate most available copper and is critical for cell survival in copper excess. d: Hippocampal neurons treated for 24 h with a 200-μM concentration of the copper chelator BCS and 50 μM glutamate. 2007. Neurosci. Atp7a traffics from cell bodies down axonal processes localizing in part with postsynaptic densities (PSD). Arrows indicate regions of Atp7a overlap. Modified from Schlief et • Copper and Iron in the Brain 321 . c: Hippocampal neurons treated for 24 h with a 200-μM concentration of the copper chelator BCS and immunolabeled for PSD-95 (green) and Atp7a (red ).annualreviews. The copper chaperone for superoxide dismutase (CCS) delivers copper to Cu/Zn superoxide dismutase (SOD1). Upon activation of NMDA receptors. Figure 3 Atp7A expression and NMDA receptor–mediated trafficking. Downloaded from www.30:317-337. Model of copper trafficking in polarized cell reveals copper entry via Ctr1 followed by distribution to the copper chaperones. For personal use only. (2005). Scale bar 150 μm. www. b: Boxed area in a enlarged as merged image of Atp7a (red ) and NeuroTrace reveals Atp7a expression in perinuclear neuronal compartment. arrowheads indicate regions distinct from PSD. Atox1 delivers copper to one of the Atpases (Atp7a/Atp7b) in the late Golgi and by University of California . 5 μM glycine. Cu / Zn SOD Cu excretion Holocuproprotein Figure 2 Cellular copper homeostasis.Berkeley on 04/10/12. Rev.

1993. Rev. Roth). d: Prussian blue stain of putamen in aceruloplasminemia reveals iron accumulation in astrocytes and neurons (arrowheads) with neuronal loss (arrows) (Morita et al. arterial tortuosity. and neuropathologic examination demonstrates focal degeneration of the gray matter and neuronal loss most prominent in the hippocampus and cerebellum (Barnard et al. b: Copper accumulation in Wilson disease visible as Kayser-Fleischer rings in Descemet’s membrane at the limbus of the cornea (Gitlin 2003). The neurologic features are present in early by University of California . 1993). Synaptic NMDA receptor activation results in rapid and reversible trafficking of Atp7a in cultured hippocampal neurons in association with copper release. 1997). 1997. Menkes disease is an X-linked disorder characterized by growth failure. Downloaded from www. the mechanisms of neurodegeneration Figure 4 Pathology in copper and iron disorders of the brain. and neuronal degeneration due to loss-of-function mutations in the gene encoding Atp7a (Chelly et al. Menkes Disease Annu. 2005) (Figure 3). The pleiotropic features of this disease are the result of impaired activity of specific cuproenzymes resulting from impaired Atp7a function (Figure 2). a: Section of cerebellum from Menkes patient brain reveals abnormal Purkinje cell with axonal swelling and arborization (courtesy of K. brittle hair. Magnetic resonance imaging of the brain reveals deficient myelination with cerebellar and cerebral atrophy (Geller et al. 322 Madsen · Gitlin . 1991) (Figure 4). Mercer et al.annualreviews. Neurosci. 2007. For personal use only. Leventer et al.activation of calcium-dependent cascades that contribute to synaptic plasticity (Lu et al. c: Coronal brain section in aceruloplasminemia reveals cavitary degeneration and discoloration of basal ganglia (arrowheads). revealing a critical role for Atp7a and copper in neuronal development (Mercer 1998).Berkeley on 04/10/12. Vulpe et al. Although several of the known cuproenzymes play critical roles in brain biochemistry. hypopigmentation. 1993. 1995). Okeda et al. 1978.30:317-337. suggesting the presence of a mechanism linking copper homeostasis and neuronal activation within the brain (Schlief et al. 2001).

infertility (Ho et al.30:317-337. The mechanisms of this hierarchy are unclear but this process illustrates copper’s essential role in brain development. 2006). and eventual copper overload in all tissues (Figure 4) (Gitlin 2003. 2003) Embryonic lethality: cardiac failure (normal CNS) (Czyzyk et al. 1995). These data suggest a model whereby loss of Atp7a contributes to both seizures and neuronal degeneration in affected patients and raise the possibility of therapeutic approaches based on NMDA receptor blockade (Hardingham & Bading 2003. 2001).org • Copper and Iron in the Brain 323 . 2005). Schlief & Gitlin 2006). hypotension. This protein is synthesized www. and the absence of Atp7a activity in Menkes disease markedly accentuates NMDA receptor–mediated excitotoxicity in these neurons (Schlief et by University of California . leakage of copper into the plasma.annualreviews. hypoglycemia Encephalopathy. 1993. 1993). in Menkes disease are unknown and not explained by impaired activity of any of these enzymes (Table 2). 2000) and when treated with copper evidence neurodevelopmental improvement (Christodoulou et al. 1998) Parenchymal iron overload. This clinical observation reveals a hierarchy of copper distribution preferential to the brain under circumstances of limited copper availability. Ceruloplasmin is an essential ferroxidase that contains greater than 95% of the copper present in plasma.annualreviews. a concept supported by recent observations in a zebrafish model of Menkes disease (Mendelsohn et al. Rare patients with some residual Atp7a activity have less central nervous system pathology despite significant systemic disease (Moller et al. Systemic copper treatment is not effective in patients with Menkes disease because copper transport into the brain is dependent on Atp7a. Wilson Disease Wilson disease is an autosomal recessive disorder resulting in hepatic cirrhosis and progressive basal ganglia degeneration due to loss-of-function mutations in the gene encoding the copper-transporter Atp7b (Bull et al. Although Atp7b is expressed in some regions of the brain. cardiac failure—neonate Consequences of loss Tyrosinase Lysyl oxidase1 Peptidylglycine α-amidating mono-oxygenase Cu/Zn superoxide dismutase Ceruloplasmin Hephaestin Annu. neurodegeneration Impaired iron absorption. Yamaguchi et al. The resulting impairment in biliary copper excretion leads to hepatocyte copper accumulation. anemia diabetes. 2005) Impaired pulmonary defenses to paraquat. Kaler et al. Neurosci. Dopamine β hydoxylase Cytochrome c oxidase 1 Consists of family of five known genes in humans. 2005). copper dependence and function of other members are not yet clearly elucidated. 1998. activation of cell-death pathways.Berkeley on 04/10/12. 1999) Impaired sympathetic regulation. 2006). releasable pool of copper in hippocampal neurons (Schlief et al. Schumacher et al. Atp7a mediates the availability of an NMDA receptor–dependent. Rev. muscle weakness. 2001. in Wilson disease copper overload in extrahepatic tissues is due to excess accumulation from the plasma following liver injury because this is entirely reversed following liver transplantation (Emre et al. Studies in a murine model of Menkes disease suggest a role for Atp7a and copper in axon extension and synaptogenesis during development (El Meskini et al. copper-mediated liver damage. For personal use only. Downloaded from www. Tao 2003). anemia (Vulpe et al. Tanzi et al.Table 2 Enzyme The cuproenzymes Function Melanin formation Collagen and elastin cross link formation Activation of peptides with α terminal glycine Antioxidant defense (superoxide dismutation) Ferroxidase Ferroxidase Norepinephrine synthesis Oxidative phosphorylation Albinism Perinatal death: arterial aneurysms. 1993. 2007. diaphragmatic rupture (Hornstra et al.

and oxygen transport (Ponka 1999). consistent with the neuropathologic findings of basal ganglia copper accumulation and neurodegeneration (Oder et al. neurotransmitter production. Although such neurological features may initially be subtle. but the precise mechanisms of cellular injury are unknown. nitric oxide metabolism. Dysfunction results in cytosolic copper accumulation with associated cellular damage. Copper transport to the trans-Golgi network (TGN) is shown as the process mediating intracellular homeostasis by Atp7b. For personal use only. Model of the proposed pathways and proteins relevant to copper metabolism in the human hepatocyte. In Wilson disease. are clearly the result of brain copper 324 Madsen accumulation because prompt improvement is observed upon treatment with oral chelating agents to restore copper homeostasis.Hepatocytes Normal Figure 5 Pathogenesis of Wilson disease. These abnormalities. although without neuropathologic correlates. Downloaded from www. without chelation patients will progress to severe Parkinsonian symptoms. Neurosci. Ceruloplasmin Wilson disease Apoceruloplasmin Mitochondrion ER Mitochondrial damage TGN TGN by University of California . Psychiatric symptoms are also common and range from behavioral problems to psychosis (Dening 1991). Neurodegeneration in Wilson disease results directly from copper accumulation. As a result. Although numerous · Gitlin . 2007. The observation that brain iron content is increased in patients with Parkinson disease and other neurodegenerative disorders has created significant interest in the possibility that disturbances of brain iron homeostasis may contribute to the pathogenesis of these diseases (Thomas & Jankovic 2004). Almost half of all patients with Wilson disease present with signs and symptoms of neuropsychiatric illness (Gollan & Gollan 1998). 1991). Bile Atox1 ER Cellular Injury Atp7b Metallothionein Ctr1 Ctr1 in hepatocytes and secreted into the plasma following the incorporation of six copper atoms in the late secretory pathway. IRON Overview Iron is required as a cofactor in central nervous system metabolic processes including oxidative phosphorylation. Rev.Berkeley on 04/10/12.annualreviews. the serum ceruloplasmin concentration is a useful diagnostic indicator of Wilson disease (Hellman & Gitlin 2002).30:317-337. loss of function of Atp7b results in synthesis of apoceruloplasmin that is rapidly degraded in the plasma (Figure 5). The reversible nature of many of these psychiatric symptoms is consistent with the concept that copper can modulate synaptic function (Schlief & Gitlin 2006) and suggests novel avenues for investigation in common psychiatric disorders.

and the genetic basis of many of these disorders has been characterized (Andrews 2002).org by University of California . Neurosci. Zecca et al. Pietrangelo 2006a) (Figure 6). For personal use only. and iron stores (Nemeth & Fe3+ Hepcidin Steap3 Fe3+ Ceruloplasmin Cu L Ferroportin Fe 2+ Frataxin S S Transferrin receptor H L Ferritin H Transferrin Fe 2+ Heme Mitoferrin DMT1 Figure 6 Pathways of cellular iron homeostasis. 2004. a causative role for impaired iron homeostasis has yet to be established in these more common neurodegenerative diseases. inflammation. erythropoietic needs. genetic disorders resulting in loss of function of these proteins rarely result in either brain iron overload or deficiency or neurologic disease. interest in this neuropathology has focused increased attention on elucidating the mechanisms of brain iron homeostasis and on defining iron’s role in neurologic disease. 2004). clinical and experimental studies have attempted to address this issue. and frataxin is a mitochondrial protein mediating Fe-S cluster formation and heme biosynthesis. mediating uptake and degradation of this exporter. These observations suggest the presence of unique mechanisms regulating iron metabolism within the central nervous system. and ceruloplasmin is a ferroxidase mediating efficient cellular iron • Copper and Iron in the Brain 325 . Central to this process is the hepatocyte-derived peptide hepcidin. The most compelling feature of systemic iron homeostasis is that iron requirements far exceed the gastrointestinal absorption capacity. Although many of the proteins shown to be essential for systemic iron homeostasis are expressed within the brain (Wu et al. Steap3 is a ferrireductase critical for transferrin-mediated iron release into the cell. The inherited diseases of iron metabolism are more common and more numerous than those of copper.annualreviews. Rev. which regulates iron availability in response to hypoxia. Iron uptake can occur via the transferrin receptor and the divalent transporter DMT1. 2004.30:317-337. and thus almost all the iron utilized each day is continuously recycled from internal stores (Koury & Ponka 2004) (Figure 7). patients with mutations that impair this protein’s function have no evidence of brain iron accumulation (Pietrangelo 2006b). Iron homeostasis is regulated by hepcidin.annualreviews. a circulating peptide that binds to ferroportin. whereas ferric iron (Fe3+ ) enters cells via endocytosis of the transferrin receptor following binding to transferrin (Andrews & Schmidt 2006). 2007. Iron enters mitochondria via mitoferrin. Downloaded from www. Iron Metabolism Genetic analysis of the inherited iron metabolism disorders has identified many of the proteins necessary for systemic iron homeostasis (Hentze et al.Annu. Ferritin is the predominant storage protein consisting of heavy chains with ferroxidase activity and light chains. Nevertheless. although ferroportin is abundantly expressed in the brain microvasculature and is the only known cellular iron exporter. Ferrous iron (Fe2+ ) is taken up into cells by the divalent membrane transporter DMT1. For example. Ferroportin is the only known cellular iron exporter.Berkeley on 04/10/12. www.

which is the primary determinant of gastrointestinal iron absorption and iron release from reticuloendothelial stores (Nemeth et al. In aceruloplasminemia. For personal use only. The brain iron cycle consists of glia and neurons. excess iron accumulation damages glia. Fe 3+ Ceruloplasmin b Neuron Neuron Bloodbrain barrier Transferrin receptor Fe 2+ Aceruloplasminemia Brain iron cycle DMT1 Ceruloplasmin Ferritin Fe 3+ Glia Transferrin Figure 7 Glia Neuroferritinopathy Iron cycles and the pathogenesis of brain iron disease. 2004). a: Systemic iron cycle allows for rapid utilization of iron and is dependent on ceruloplasmin to establish a rate of iron oxidation sufficient for mobilization from reticuloendothelium. Ceruloplasmin plays a critical role in this pro326 Madsen cess by establishing a rate of plasma iron oxidation sufficient for the continued release of this metal from the storage sites (Harris et al. Iron is taken up into the brain from the plasma via transferrin receptor–mediated endocytosis in the brain capillaries and returned · Gitlin . 2007. or accumulation of nontransferrin-bound iron. iron-deficiency. Hepcidin binds to and induces the endocytosis and turnover of the plasma membrane iron exporter ferroportin.Berkeley on 04/10/ by University of California . 1998) (Figure 7). where gpi-linked ceruloplasmin functions in a similar role as in the periphery. Downloaded from www.30:317-337. Rev.a Erythropoiesis Erythrocytes Liver Spleen Reticuloendothelial cells Ferroportin Fe 2+ Bone marrow Iron cycle Transferrin Annu. b: Iron crosses the blood brain barrier via transferrin receptor pathway on endothelium. Ganz 2006).annualreviews. Neurosci. A similar pathogenesis is proposed for neuroferritinopathy. and neurons are subsequently injured from loss of glia-derived factors.

Morita et al.30:317-337.Annu. The inherited disorders aceruloplasminemia and neuroferritinopathy support the concept of a brain iron cycle and demonstrate that dysregulation of brain iron homeostasis can be a primary cause of neurodegeneration (Ponka 2004) (Table 3). Iron requirements in the brain are much greater than the observed rate of iron uptake into this tissue (Bradbury 1997). 2007. 1987. to circulation via absorption of cerebrospinal fluid (Moos et al. 2005). and dystonia secondary to basal ganglia iron accumulation (Logan et al.annualreviews. elevated serum ferritin. Patients have absent serum by University of California . decreased serum iron. 1995). The neurologic disease in aceruloplasminemia is always associated with increased brain iron as detected by magnetic resonance imaging or autopsy (Kono & Miyajima 2006). 1995. suggesting a role in brain iron storage and distribution (Haacke et al. Yoshida et • Copper and Iron in the Brain 327 . This mechanism would protect the brain from the effects of systemic iron overload or deficiency and is supported by observations that disturbances of systemic iron homeostasis exhibit minimal effects on central nervous system iron content or metabolism (Moos & Morgan 2004). Miyajima et al. anemia. supporting the idea that these cells and other types of glia function in iron storage and regulation.annualreviews. dementia Dystonia. Aceruloplasminemia Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis caused by loss-of-function mutations in the ceruloplasmin gene (Harris et al. this concept indicates that following birth recycling. is the major iron source for brain function (Lozoff et al. Rev. Nittis & Gitlin 2002). dysarthria. 2006). The rate of brain iron uptake is greatest during fetal life and postnatal iron repletion is ineffective to correct the cognitive defects arising from iron deficiency in utero. dystonia. dysarthria Brain iron storage Brain iron accumulation Neuroferritinopathy Autosomal dominant (dominant-negative) mutations ferritin light chain gene Third through sixth decade www. Histological findings from affected brain regions The hereditary disorders of brain iron metabolism Aceruloplasminemia Autosomal recessive loss-of-function mutations ceruloplasmin gene Third decade—diabetes Fifth decade—neurologic Brain iron recycling Brain iron accumulation Systemic iron accumulation Diabetes. 1995). Brain iron accounts for less than 2% of the total body iron content and varies greatly in amount and concentration depending on the specific region of the brain. For personal use only. The concentration of iron in the brain is greatest in the basal ganglia where it is equivalent to that found in the liver. anemia. Despite these systemic features. Existence of this brain iron cycle has critical implications for interpreting any finding of brain iron accumulation in disease. and insulin-dependent diabetes mellitus (Gitlin 1998. Table 3 Genetics Presentation Defect Pathogenesis Clinical Pathology rather than uptake from the circulation. most patients present with progressive dementia. Iron is widely distributed in all cell types within the central nervous system but is abundant especially in astrocytes. Downloaded from www. Neurosci. This finding suggests most brain iron used each day is derived from recycling behind the bloodbrain barrier analogous to what occurs in the periphery (Figure 7). 2006). dysarthria Iron accumulation in astrocytes Neuronal loss Iron accumulation in astrocytes Neuronal loss Dementia. 1994.Berkeley on 04/10/12.

2004) (Figure 7). Neuroferritinopathy Ferritin is a ubiquitously expressed cytoplasmic iron storage protein consisting of heavy and light chains encoded on separate genes (Figure 6). all patients with neuroferritinopathy evidence dystonia in association with basal ganglia iron accumulation (Chinnery et al. an autosomal dominant extrapyramidal disease resulting from mutations in the gene encoding the light chain of ferritin. 2007). This mechanism of systemic iron accumulation also occurs in patients with dominant-negative mutations in the gene encoding the iron exporter ferroportin (De Domenico et al. Hentze et al. Iron-dependent translational regulation of this protein by the cytosolic iron regulatory proteins Irp1 and Irp2 ensures that ferritin is a readily available source of intracellular iron in all cells including neurons and glia (Rouault 2006). Ceruloplasmin is one of very few proteins established as playing a critical role in brain iron homeostasis. The absence of ceruloplasmin results in the slow accumulation of iron in the reticuloendothelial cells where this metal is normally stored and then mobilized for recycling (Harris et al. Loss of ceruloplasmin also results in increased nontransferrinbound iron that rapidly accumulates in the liver. 2000). 2002. and iron and ferritin in both extracellular and cytoplasmic inclusion bodies of microglia.30:317-337. 2005. ceruloplasmin is synthesized in astrocytes (Klomp et al. · Gitlin . Neuroferritinopathy. owing to loss-of-function mutations in ferroportin that impair hepcidin regulation inappropriately increasing nontransferrin-bound iron (De Domenico et al. 2002) (Figure 7). This finding suggests either a unique role for the Annu. 1995. The absence of brain iron accumulation in other diseases with increased nontransferrinbound plasma iron supports the idea that brain iron accumulation in aceruloplasminemia results directly from impaired iron homeostasis within the central nervous system. For personal use only. 1996. 2006).Berkeley on 04/10/12. 2007). 2001. 2004). Rev. 2005). Consistent with this concept. neuronal loss. where excess iron absorption elevates nontransferrin-bound plasma iron (Andrews 2002).org by University of California . and excess iron deposition in glia and neurons (Kaneko et al. in the thalassemias and other forms of secondary iron overload. has revealed a primary role for ferritin in brain iron homeostasis (Curtis et al. Downloaded from www. Pathological examination of affected patients reveals cavitary degeneration in the basal ganglia nuclei.include neuronal cell loss. 2007. Patients with neuroferritinopathy express the ferritin light chain mutation in all cells yet evidence no abnormalities in systemic iron homeostasis with the exception of decreased serum ferritin (Chinnery et al. 2006) (Figure 4). 2005. Although there are some phenotype-genotype correlations specific to each light chain mutation. suggesting that this membrane-bound ferroxidase facilitates the rate of iron release from storage cells within the central nervous system. 1999. Although these disorders of iron metabolism share common mechanisms of tissue iron overload. Klomp & Gitlin 1996) as 328 Madsen a glycophosphatidylinositol-linked isoform (Jeong & David 2003. where transfusiondependency elevates nontransferrin-bound plasma iron (Pietrangelo 2006b). and in hemochromatosis. pancreas. This mechanism of tissue iron accumulation also occurs in atransferrinemia. and other tissues following removal from the plasma by DMT1 (Andrews 2002. Patel et al. abnormal astrocyte architecture. Morita et al. Maciel et al. 1987).annualreviews. Patel et al. Neurosci. where the absence of serum transferrin increases the relative amount of nontransferrin-bound plasma iron (Craven et al. Vidal et al. Oide et al. The autosomal dominant inheritance and the multimeric structure of ferritin suggest that these mutations impair ferritin assembly resulting in loss of iron storage capacity within brain cells and subsequent iron-mediated cell injury (Levi et al. in HFE hemochromatosis. accumulation of iron in the brain is unique to aceruloplasminemia. 2006). Mancuso et al.

Rev. 1996) due to loss of function of frataxin. 2001). ferritin light chain in some cell types within the brain or a greater sensitivity of these cells to this form of iron-dependent injury. and pigmentary retinopathy and have autosomal recessive. 2003). the similar pathology to aceruloplasminemia suggests a role for ferritin in the brain iron cycle and implies a common iron-dependent mechanism of neurodegeneration in these two diseases (Figure 7). Although not specific to the brain. Chelation is an effective therapy in such individuals. Recent studies in aceruloplasminemia suggest that neuronal loss in this disease arises from iron deficiency secondary to impaired iron movement from astrocytes within the brain iron cycle ( Jeong & David 2006). Lill & Muhlenhoff 2006). much more needs to be learned about the normal mechanisms of copper homeostasis in www. in the pathogenesis are unknown. a transporter expressed in the inner mitochondrial membrane (Shaw et al. 1997). Iron is imported into mitochondria by mitoferrin. Friedreich’s Ataxia Friedreich’s ataxia is an autosomal recessive disorder characterized by sensory neuron. loss-of-function mutations in the gene-encoding mitochondrial pantothenate kinase 2. Voncken et al. Although elucidation of the genetic basis of Menkes and Wilson diseases has revealed much about the cell biology of copper metabolism. Most of these patients present in childhood with dystonia. an essential mitochondrial enzyme involved in coenzyme A biosynthesis (Hayflick et al.30:317-337.Annu. Downloaded from www. Mitochondrial iron is required for heme biosynthesis and for the generation of Fe/S clusters that are prosthetic groups in many essential enzymes ¨ (Ajioka et al. cerebellar. Support for a similar mechanism in neuroferritinopathy comes from a murine model of Irp2 deficiency that impairs ferritin by University of California . The mechanisms of psychiatric disease observed in patients with Wilson disease are of particular interest. Neurodegeneration with Brain Iron Accumulation Neurodegeneration with brain iron accumulation describes a heterogeneous group of patients with progressive neurodegeneration and iron deposition in the basal ganglia (Gregory & Hayflick 2005. For personal use only. results in iron accumulation within oligodendrocytes. impairment of heme and Fe/S cluster biosynthesis is CONCLUSIONS The inherited disorders of copper metabolism reveal copper’s essential role in brain development and neuropsychiatric disease. indicating copper’s direct role in pathogenesis and suggesting avenues for study that may be widely applicable to brain function and mental health. 2006.Berkeley on 04/10/12. 2004. and exits mitochondria largely in the form of Fe/S clusters (Rouault & Tong 2005). a mitochondrial protein involved in inorganic iron-sulfur (Fe/S) cluster biogenesis (Babcock et al. 2007. • Copper and Iron in the Brain 329 . 2006).annualreviews. the effect of impaired mitochondrial iron homeostasis on neuronal survival in this disease warrants mention here. and leads to neurodegeneration most likely from secondary neuronal iron deficiency (LaVaute et al. if any. Zhou et al. 2006). Hayflick et al. However. the likely proximate cause of neurodegenera¨ tion in Friedreich’s ataxia (Lill & Muhlenhoff 2006. these disorders deserve mention because recent studies reveal mutations in the gene encoding a calcium-independent group VI phospholipase A2 in some children with brain iron accumulation and neurodegeneration. Neurosci. 2001). Although the mechanism of neurodegeneration in neuroferritinopathy is unknown. and cardiomyocyte degeneration (Durr et al.annualreviews. Although excess mitochondrial iron is detected in cardiomyocytes and sensory neurons from affected patients (Puccio et al. Johnson et al. The mechanisms of iron accumulation and the role of iron. 2004). suggesting a novel link between phospholipid and iron metabolism in the brain (Morgan et al. dysarthria. 2001).

caution is warranted because more knowledge of copper homeostasis within the brain and copper’s role in specific neurologic functions is required before any such therapeutic approaches can be thoughtfully undertaken or interpreted. The discovery of aceruloplasminemia and neuroferritinopathy demonstrates that dysregulation of brain iron homeostasis can be a primary cause of neurodegeneration. ACKNOWLEDGMENTS The study of copper and iron disorders of the brain in J. Phillips JD. 1978. 1997. Transport of iron in the blood-brain-cerebrospinal fluid system. Doraiswamy & Finefrock 2004. Zecca et al. Biochim. Oaks R. Annu. Neurochem. Biophys.Annu. Copper homeostasis in eukaryotes: teetering on a tightrope.’s laboratory is supported by the National Institutes of Health (DK44464. A cautionary tale is also provided by the numerous iron chelator and antioxidant trials initiated in patients with Friedreich’s ataxia on the basis of the findings of mitochondrial iron accumulation. Schaffner by University of California . 2006. 1997. Schmidt PJ. Biochim. Rev.Berkeley on 04/10/12. Acta 1763:723–36 Andrews NC. Davis-Kaplan S. the brain. mechanistic approaches to defining disease pathogenesis when normal physiology remains poorly understood. Semin Hematol. including the proposed treatment of affected patients with metal chelating drugs (Bush 2000. Science 276:1709–12 Balamurugan K. de Silva D. However. Iron homeostasis. 69:443–54 330 Madsen · Gitlin . et al. absent further understanding of the molecular mechanisms of iron homeostasis in the central nervous system. none of which have any demonstrated clinical benefit in doubleblind placebo-controlled trials. Dev. 2006). was supported by NIH Medical Scientist Training Program grant T32 GM07200. HD39952). Physiol. Kushner JP. Neuropathology of Menkes’ disease. Regulation of mitochondrial iron accumulation by Yfh1p. Rev. Med. Gaeta & Hider 2005). LITERATURE CITED Ajioka RS. Best PV. These inherited disorders provide a platform for further mechanistic investigations that should reveal new insights into brain iron homeostasis. 39:227–34 Andrews NC. For personal use only. Nevertheless. Neurosci. Biosynthesis of heme in mammals. attention is given to recent studies identifying a signaling cascade in neurons where stimulation of NMDA receptors mediates iron uptake via the divalent iron transporter DMT-1. a putative homolog of frataxin. Erdohazi M. Jiralerspong S. Recent studies have focused on copper’s role in the pathogenesis of prion-mediated encephalopathy and Alzheimer disease. J. Biophys. Acta 1763:737–46 Barnard RO.G. A genetic view of iron homeostasis. 2006. Downloaded from www. 2007. investigators currently cannot interpret the significance of iron accumulation in the pathogenesis of other neurologic diseases (Lee et al. the role of the basal ganglia in copper and iron storage and distribution needs further study as do the mechanisms of this brain region’s vulnerability to excess copper and iron. This concept is illustrated by recent studies in aceruloplasminemia that suggest that neurodegeneration arises from iron deficiency despite the marked brain iron overload. These data remind us of the need for critical. E. 2007. DK61763. In this regard.30:317-337. 2004). 2006. 69:69–85 Babcock M. Child Neurol. 20:586–97 Bradbury MW. 2002. In particular. This work provides a physiologic link between neuronal function and iron homeostasis and suggests mechanisms linking iron and NMDA neurotoxicity that would direct future investigation (Cheah et al.

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