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Role of copper in human neurological disorders
1–3
Vishal Desai and Stephen G Kaler 
ABSTRACT
Copper is a trace element present in all tissues and is required forcellular respiration, peptide amidation, neurotransmitter biosynthe-sis, pigment formation, and connective tissue strength. Copper is acofactorfornumerousenzymesandplaysanimportantroleincentralnervous system development; low concentrations of copper mayresult in incomplete development, whereas excess copper maybeinjurious.Coppermaybeinvolvedinfreeradicalproduction,viatheHaber-Weiss reaction, that results in mitochondrial damage, DNAbreakage, and neuronal injury. Evidence of abnormal copper trans-port and aberrant copper-protein interactions in numerous humanneurological disorders supports the critical importance of this tracemetal for proper neurodevelopment and neurological function. Thebiochemical phenotypes of human disorders that involve copperhomeostasis suggest possible biomarkers of copper status that maybe applicable to general populations.
Am J Clin Nutr 
2008;88(suppl):855S–8S.
INTRODUCTION
Copperisoneofmanymetalionsthatarerequiredforessentialbody functions but are toxic in excess (1, 2). Copper is presentthroughout the brain and is most prominent in the basal ganglia,hippocampus, cerebellum, numerous synaptic membranes, andin the cell bodies of cortical pyramidal and cerebellar granularneurons (2). Enzymes in the central nervous system that dependon copper for their function include tyrosinase, peptidylglycine
-amidating mono-oxygenase, copper/zinc superoxide dis-mutase, ceruloplasmin, hephaestin, dopamine-
-hydoxylase,andcytochrome
c
oxidase(3–5).Copperisimplicateddirectlyorindirectlyinthepathogenesisofnumerousneurologicaldiseases,includingaceruloplasminemia,Alzheimerdisease,amyotrophiclateral sclerosis, Huntington disease, Menkes disease, occipitalhorn syndrome, Parkinson disease, prion disease, and Wilsondisease (
Table 1
). In this review, we provide an overview of current knowledge about the effect of copper deficiency andexcessonthebrainandneuraltissuesthroughthecontextofthesedisorders and suggest possible biomarkers of copper status thatmay be applicable to population screening.
ACERULOPLASMINEMIA
Ceruloplasmin contains 95% of the copper in plasma and itfunctionsasaferroxidase.Deficiencyisassociatedwithprogres-sive iron accumulation involving the retina and basal ganglia.Aceruloplasminemia is an autosomal recessive condition (6, 7).Copper does not directly affect the rate of synthesis or the secre-tion of ceruloplasmin; however, failure to incorporate copperinto apoceruloplasmin results in an unstable apoprotein that israpidly degraded (8). The clinical consequences of aceruloplas-minemiaincludedystonia,abnormalgait,dysarthria,anddemen-tia.
ALZHEIMER DISEASE
Progressive cognitive impairments are characteristic in thedementia of Alzheimer disease. An increased concentration of copper in cerebrospinal fluid with normal plasma copper con-centrations has been noted in some patients with Alzheimer dis-ease (9). Copper interacts with amyloid precursor protein and
-amyloid peptide in the self-aggregating plaques and neurofi-brillary tangles characteristic of Alzeimer disease and may con-tribute to the pathogenesis of this disorder via cellular oxidativestress (2, 3, 10–13).
AMYOTROPHIC LATERAL SCLEROSIS
Gain-of-function mutations in the cytosolic copper enzymeCu/Zn-superoxide dismutase result in motor neuron degenera-tioncharacteristicofamyotrophiclateralsclerosis.Thisselectiveneuronaldamageleadstolossofmusclestrengthandrespiratoryproblems, with an eventual fatal outcome (9). Some evidencesuggests a direct pathogenic role for copper in this process; en-hanced free radical generation is suspected (2, 6, 9, 14). Amyo-trophic lateral sclerosis is considered a model disorder for neu-rodegeneration involving deterioration of the anterior horn cellsin the spinal cord.
HUNTINGTON DISEASE
Huntingtondiseaseiscausedbyatripletrepeatexpansionofaprotein (huntingtin) that leads to oxidative stress, energetic in-sufficiency,andstriataldegeneration.Elevatedconcentrationsof copper are found in human Huntington disease brain (15). It ishypothesized that increased amounts of copper bound to lowaffinity binding sites in huntingtin promote oxidant stress andneurodegeneration.
1
From the Unit on Pediatric Genetics, Program in Molecular Medicine,National Institute of Child Health and Human Development, National Insti-tutes of Health, Bethesda, MD.
2
Presented at the symposium “Molecular Biomarkers of Copper Ho-meostasis,” held in Vin˜a del Mar, Chile, September 26–29, 2007.
3
Address reprint requests to SG Kaler, Building 10, Room 5-2571, 10Center Drive MSC 1832, Bethesda, MD 20892-1832. E-mail:kalers@mail.nih.gov.
855S
 Am J Clin Nutr 
2008;88(suppl):855S–8S. Printed in USA. © 2008 American Society for Nutrition
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MENKES DISEASE
Menkesdiseaseisaninfantileneurogeneticdisordercausedbymutations in an X-linked gene,
ATP7A
(1, 2, 4, 5, 16–21). Thisgene encodes a copper-transporting P-type ATPase, so namedbecause it forms a covalently phosphorylated intermediate fromtransfer of the gamma-phosphate of ATP to a specific aspartateresidue at the catalytic site of the protein. Deficiency of the
 ATP7A
gene product results in abnormal cellular copper trans-port and decreased activities of numerous copper-dependent en-zymes. Persons with Menkes disease have a defect in coppertransport across the placenta, gastrointestinal tract, and blood-brain barrier. Circulating concentrations of copper and cerulo-plasmin are low, and neurochemical concentrations affected bythe copper enzyme dopamine-
-hydroxylase, are distinctivelyabnormal (17, 18, 21). Decreased activity of the copper-dependentenzymecytochrome
c
oxidaseislikelyamajorfactorin the brain damage associated with Menkes disease. Becausecopper is a noncompetitive antagonist of the
N 
-methyl-
D
-asparatereceptor,itmayalsohavearoleinregulationofneuronalexcitability. Synaptic
N 
-methyl-D-asparate receptor activationresults in rapid and reversible trafficking of ATP7A, which sug-gestsalinkbetweencopperhomeostasisandneuronalactivationwithinthebrain(2).Despitetheknownassociationofanemiaandsevere copper deficiency (22), Menkes disease patients rarelyhave hematologic manifestations.ATP7A plays a significant role in the development and main-tenance of the central nervous system, which can be seen by themarked behavioral, neurological, and developmental abnormal-ities observed in Menkes disease patients. ATP7A serves as acopper transporter in vascular endothelial cells and retinal pig-ment epithelium forming the blood-brain barrier and is thus im-portant for delivery of copper to the brain. Patients with Menkesdisease show progressive cerebral atrophy and delayed myeli-nation on magnetic resonance imaging of the brain. At autopsy,diffuse atrophy, focal gray matter degeneration, prominent celllossinthecerebellum,abnormaldendriticarborization,andfocalaxonal swelling are noted.The neurological phenotype of Menkes disease involves pro-found truncal hypotonia with poor head control. Deep tendonreflexes are hyperactive, and visual fixation and tracking areoften impaired. The natural history of the disease often involvesdeath by 3 y of age.
OCCIPITAL HORN SYNDROME
Occipitalhornsyndromeisaneurologicallylesssevereallelicvariant of Menkes disease with connective tissue problems in-cluding cutis laxa, hyper-mobile joints, and bony protuberancesoftheocciput(5,23,24).Thesefindingsarerelatedtodecreasedlysyl oxidase activity, which leads to disruption of collagen and
TABLE 1
Neurological diseases involving copper metabolismDisease Characteristics Neuronal effectsAceruloplasminemia Autosomal recessive trait Progressive neurodegeneration (retina, basal ganglia)Absence of ceruloplasmin Dystonia/abnormal gait, dysarthria, dementiaAccumulation of iron (liver, pancreas, basalganglia)Alzheimer disease (AD) Mutations in amyloid precursor protein causefamilial ADAccumulation of amyloid
proteinAdult-onset dementia and behavioral changes Self-aggregating plaques and neurofibillary tanglesMost common over 65 y of age Associated with cellular oxidative stressAmyotrophic lateral sclerosis Gain-of-function mutations in Cu/Zn superoxidedismutatse cause small percentage of casesDegeneration of upper and lower motor neuronsAdult-onset progressive muscle weakness Death ultimately due to respiratory failureHuntington disease Autosomal dominant trait Polyglutamine triplet repeat expansionTeenage- or adult-onset Pro-oxidative activitiesSevere movement disorder Nigrostriatal neurodegenerationMenkes disease X-linked recessive gene Progressive cerebral atrophyPoor copper absorption and distribution DysmyelinationConnective tissue problems Abnormalities of intracranial vesselsOccipital horn syndrome Mild allelic variant of Menkes Mild cerebral atrophySymptoms of dysautonomia Slightly delayed myelinationConnective tissue problemsParkinson disease Primary movement disorder Death of dopaminergic neuronsBradykinesia/akinesia Accumulation of intracellular inclusionsMuscular rigidity/tremor (Lewy bodies)Prion diseases Transmissable neurodegenerative disease Result of modified PrPs:PrP
Sc
and PrP
M
Spongiform encephalopathy Possible inappropriate metallation of PrP withMn instead of CuWilson disease Autosomal recessive Predilection for copper accumulation in basal gangliaCarrier frequency: 1 in 90Clinical presentation Neuronal loss, gliosis, and cavity degenerationHepatic versus neurologicAge-influenced
1
PrP, prion protein; PrP
Sc
, prion protein scrapie variant; PrP
M
, prion protein mutant form.
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DESAI AND KALER
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elastin cross-linking. As in Menkes disease, dopamine-
-hydroxylase activity is decreased in occipital horn syndrome,producing symptoms of dysautonomia (25, 26). The autonomicnervous system is involuntary and plays a crucial role in themaintenanceofhomeostasisthroughinnervationofcardiacmus-cle,smoothmuscle,andendocrineandexocrineglands(26).Theautonomic nervous system has 2 divisions: the sympathetic andthe parasympathetic systems. Both are tonically active, and thefrequency of discharge of neurons in both systems can increaseor decrease. With diminished production of norepinephrine,there is impaired innervation of postganglionic sympathetic tar-gets. This may produce bradycardia, orthostatic hypotension,and chronic diarrhea in persons with occipital horn syndrome(23–25). The overall biochemical phenotype (low serum copperandceruloplasminandabnormalplasmaandcerebrospinalfluidcatecholamine concentrations) is similar to that seen in Menkesdisease, although often less severe.
PARKINSON DISEASE
Parkinsondiseaseisacommonneurodegenerativemovementdisorder characterized by impaired motor function, includingresting tremors, rigidity, bradykinesia, and postural instability(27). The pathophysiology of Parkinson disease includes dopa-minergic neuron death and accumulation of Lewy bodies asso-ciated with mutations in
-synuclein, a 14-kDa protein predom-inantly expressed in the central nervous system (27, 28).Oxidative injury appears to be one effect of 
-synuclein aggre-gatesandcouldultimatelyproduceneuronalcelldeath(27).Thekinetics of 
-synuclein aggregation are modulated by severalfactors in vitro, including the presence of certain metal cations.Copper is the most effective in accelerating aggregation, sug-gesting a possible link between abnormal copper homoeostasisand this condition (28).
PRION DISEASES
The prion diseases are a group of neurodegenerative diseasesthat affect the gray matter of the central nervous system andproduceneuronalloss,gliosis,andspongiformdegeneration(29,30). Prion diseases are caused by prion proteins (PrPs) that havebeen modified such that they fold improperly. PrPs are highlyexpressed in the central nervous system and contain high-affinity copper-binding sites in their amino-terminal regions. Invitro, copper enhances renaturation and stabilization of PrPs,enhancing protease resistance and infectivity, and leading tospeculation about copper’s role in the pathogenesis of priondiseases (6, 30).
WILSON DISEASE
Wilson disease is an autosomal recessive disorder caused bythe loss-of-function mutations in the copper transport gene
 ATP7B
(1).Thisresultsinhepaticcirrhosisandprogressivebasalgangliadegenerationinthebrain(31).Thereisimpairmentintheabilityofcoppertobeincorporatedintoceruloplasmin,which,aspreviouslydiscussed,contains95%ofbloodcopper.Thelossof ATP7Bresultsinproductionofapoceruloplasmin,whichisrap-idlydegradedintheplasma,resultinginreducedcopper-carryingcapacity. There is concomitant impairment in excretion of cop-per into bile. This leads to hepatic copper accumulation anddamage, elevated levels of non-ceruloplasmin-bound copper inthe plasma and, ultimately, copper overload in extrahepatic tis-sues (31, 32). Copper accumulation in the basal ganglia leads toParkinsonian symptoms, including tremors and dystonia. In-deed, Wilson disease may properly be classified as a movementdisorder. In addition to liver and brain, the eye is also a primarysite of copper deposition in Wilson disease. A pathognomonicsign, the Kayser-Fleischer (KF) ring, is an annular deposition of copper in the periphery of the cornea. Copper can also accumu-lateinthelensandcause“sunflower”cataracts.About
95%of patients with a neurological presentation manifest the Kayser-Fleischer ring compared with
65% of those with a hepaticpresentation (32). Oral copper chelating agents are effective inrestoring copper homeostasis in many patients with Wilson dis-ease (31, 32).
COPPER BIOMARKERS
If reliable biomarkers of total-body copper status were avail-able, potentially undesirable health effects due to excess or de-ficiency of this trace metal could be prevented. Several biomar-kers can be considered to screen for copper deficiency. Aspreviously discussed, dopamine-
-hydroxylase (DBH), a cu-proenzyme,functionsinthesynthesisofnorepinephrine.Incop-perdeficiency,DBHactivitymaydecreaseandresultinelevatedratiosofdopaminetonorepinephrine,asseeninMenkesdisease(21). Impaired activity of DBH also leads to increased urinaryratios of homovanillic acid to vanillylmandelic acid (33). Othercuproenzymesmayalsobemeasureableaspotentialbiomarkersofcopperdeficiency.Ceruloplasmincontains95%ofthecopperfoundinplasma,andlevelsdecreaseduringseverecopperdeficit(22). Copper/zinc superoxide dismutase, cytochrome
c
oxidase,peptidylglycine
-amidatingmonooxygenase,andlysyloxidaseare all cuproenzymes whose activity or gene expression may beinfluenced by copper deficiency (34–38).We also note several potential biomarkers of copper excess.Excess copper is deposited in the liver where high levels cancauseinjury.Althoughnonspecific,thehepaticaminotransferaseenzymes, glutamic-oxaloacetic transaminase, glutamic-pryuvictransaminase, and
 
-glutamyl-transferase, are biomarkers forliver damage due to elevated copper. Interleukin-2 may also beuseful as a biomarker of copper excess; concentrations of interleukin-2 increase in response to copper supplementation(39). Urinary
2-microglobulin may also be a useful marker of copper excess (21). Binding of copper ions destabilizes native
2-microglobulin(40),andchangesinrenaltubulardysfunctionmay parallel the serum concentrations of copper (41).
CONCLUSIONS
Recentevidencehighlightstheimportantroleofcopperinthedevelopment and maintenance of the mammalian nervous sys-tem. Further advances in understanding these functions will af-fect our understanding of the human neurological disorders re-viewed here and hopefully will suggest useful therapeuticapproaches. The biochemical phenotypes associated with someofthesedisorderssuggestpotentialfordetectionofcopperexcessanddeficiencyinthegeneralpopulation.Evaluationoftheutilityof such biomarkers awaits formal population surveys.
COPPER IN HUMAN NEUROLOGICAL DISORDERS
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