The transition metals copper and iron in neurodegenerative diseases

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Chemico-Biological Interactions 186 (2010) 184–199

Contents lists available at ScienceDirect

Chemico-Biological Interactions

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he transition metals copper and iron in neurodegenerative diseases

usana Rivera-Mancíaa, Iván Pérez-Neria, Camilo Ríosa, Luis Tristán-Lópeza,iliana Rivera-Espinosab, Sergio Montesa,∗

Neurochemistry Department, National Institute of Neurology and Neurosurgery ‘Manuel Velasco Suárez’, Mexico City, MexicoPharmacology Department, National Institute of Pediatrics, Mexico City, Mexico

r t i c l e i n f o

rticle history:eceived 28 September 2009eceived in revised form 22 January 2010ccepted 8 April 2010vailable online 14 May 2010

a b s t r a c t

Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper areessential for life, but they are also involved in several neurodegenerative mechanisms such as pro-tein aggregation, free radical generation and oxidative stress. The role of Fe and Cu, their pathogenicmechanisms and possible therapeutic relevance are discussed regarding four of the most common neu-rodegenerative diseases, Alzheimer’s, Parkinson’s and Huntington’s diseases as well as amyotrophic

eywords:lzheimer’s diseasearkinson’s diseasemyotrophic lateral sclerosisuntington’s disease

lateral sclerosis. Metal-mediated oxidation by Fenton chemistry is a common feature for all those dis-orders and takes part of a self-amplifying damaging mechanism, leading to neurodegeneration. Theinteraction between metals and proteins in the nervous system seems to be a crucial factor for the devel-opment or absence of neurodegeneration. The present review also deals with the therapeutic strategiestested, mainly using metal chelating drugs. Metal accumulation within the nervous system observed

opperron

in those diseases could be the result of compensatory mechanisms to improve metal availability forphysiological processes.

© 2010 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1852. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

2.1. Fe homeostasis in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1862.2. Cu homeostasis in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1862.3. Metal-related therapies for AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1862.4. AD: concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

3. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1873.1. Fe homeostasis in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1873.2. Cu homeostasis in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1893.3. Metal-related therapies for Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1893.4. PD: concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

4. Amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
4.1. Fe homeostasis in amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . .4.2. Cu homeostasis in amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . .4.3. Metal-related therapies for amyotrophic lateral sclerosis . . . . . . . . .4.4. ALS: concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abbreviations: AD, Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’sopper-transporting P-type ATPase; TfR, transferrin receptor; DMT1, divalent metal traetalloproteinase; CHO, Chinese Hamster Ovary; CSF, cerebrospinal fluid; Cp, cerulop

ein kinase B; GSK, glycogen synthase kinase; CQ, clioquinol; GTSM, glyoxalbis(N(4)-mompacta; NMDA, N-methyl-d-aspartate; NO, nitric oxide; 6-OHDA, 6-hydroxydopamine-methyl-4-phenylpyridinium; FALS, familial amyotrophic lateral sclerosis; HFE, hemochetrathiomolybdate; Htt, Huntingtin; ESC, embryonic stem cells.∗ Corresponding author at: National Institute of Neurology and Neurosurgery ‘Manuel

Mexico. Tel.: +52 55 5606 3822x2006; fax: +52 55 5424 0808.E-mail address: [email protected] (S. Montes).

009-2797/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.cbi.2010.04.010

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

disease; ALS, amyotrophic lateral sclerosis; ROS, reactive oxygen species; ATP7A,nsporter 1; Abeta, amyloid beta; APP, amyloid precursor protein; MMP, matrixlasmin; SOD, superoxide dismutase; EGCG, epigallocatechin-3-gallate; Akt, pro-ethyl-3-thiosemicarbazonato); SN, substantia nigra; SNpc, substantia nigra pars; Ireg-1, ferroportin; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+,romatosis gene; MBR, metal-binding region; WTL, wild-type like; TTM, ammonium

Velasco Suárez’, Insurgentes Sur 3877, La Fama, Tlalpan, Mexico City 14269,

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S. Rivera-Mancía et al. / Chemico-Biological Interactions 186 (2010) 184–199 185

5. Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925.1. Fe homeostasis in Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925.2. Cu homeostasis in Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1935.3. Metal-related therapies for Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1935.4. HD: concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

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cular amyloid deposits [25,26] (Fig. 1).Transition metals are necessary for the correct functioning of

antioxidant systems in the cell; however, an increasing body ofevidence has been published regarding the role of metals in AD

Fig. 1. Copper (Cu) and iron (Fe) in Alzheimer’s disease. (1) Cu ions in the synap-tic space are co-released with glutamate. Abeta, produced from APP by secretases,possesses high affinity for Cu. Abeta and Cu ions coincide in synaptic space, possiblyinducing the precipitation of Abeta. (2) Cu is suspected to consolidate the forma-tion of senile plaques by catalyzing new covalent bonds among polypeptides. Cuis found in high quantities in amyloid plaques. (3) Intracellular Cu is involved inthe expression of matrix metalloproteinase responsible for the cleavage of Abeta.(4) High content of iron is involved with increased expression of APP through anIron Response Element (IRE), whereas depletion of copper decreases the expres-

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

In recent years, neurodegenerative diseases have become anmportant worldwide health issue. Those diseases affect the ner-ous system and share features such as selective neuronal death,rotein aggregation, oxidative stress, mitochondrial dysfunction,ransition metal accumulation and inflammation [1–5]. Neurode-enerative diseases are associated with ageing but their actualtiology remains unknown [1].

Almost all living organisms require Fe, Cu and other transi-ion metals to correctly carry out their most essential metabolicrocesses. Metals are involved in several important functions inhe nervous system: Fe is required to support the brain’s highespiratory rate as well as for myelination, gene expression andeurotransmitters synthesis [6,7]. Cu is also required for mitochon-rial respiration, neurotransmitter biosynthesis and as a cofactoror antioxidant enzymes [8].

Although transition metals are important for life, it has beenvidenced that they are also involved in neuronal damage in manyeurodegenerative disorders. Neurodegenerative diseases asso-iated with the disruption of brain metal homeostasis includelzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) diseasess well as amyotrophic lateral sclerosis (ALS) [5,9,10]. It has beenbserved that patients with neurodegenerative diseases accumu-ate metals in their nervous system [11,12], suggesting a role of

etals in those disorders. Fe homeostasis is frequently altered ineurodegenerative disorders [12,13]; under certain conditions, thisetal is the most potent pro-oxidant due to its high availability

14]. The excessive production of reactive oxygen species (ROS),xidizes proteins, DNA and phospholipids leading to structural andunctional alterations [15]. Metal-binding proteins and DNA mayherefore be vulnerable. Most of the reactions involving Fe areelated to Fenton chemistry, a series of reactions that initiates withransition metals and hydrogen peroxide leading to the formationf highly unstable radicals that affect biological macromolecules5].

Proteins involved in metal transport and distribution in theervous system, such as copper transporter protein 1 and ATP7Acopper-transporting P-type ATPase) for Cu [2,16], transferrin andransferrin receptor (TfR) for Fe, and DMT1 (divalent metal trans-orter 1) for both Cu and Fe [17], could be involved in the alteredetal homeostasis in the brain of patients with neurodegenerative

iseases.This review focuses on the role of Fe, Cu and the proteins related

o them, in the underlying mechanisms of neurodegenerative dis-ases such as AD, PD, ALS and HD, as well as some attempts thatave been carried out to treat them.

. Alzheimer’s disease

Several factors have been involved in the etiology of AD: aging,xidative stress and brain metal accumulation. This disorder isharacterized by memory impairment, progressive decline in cog-itive function and dementia [18]. The increasing prevalence of

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dementia [19] is a matter of public health and social concern sincenowadays there is no effective treatment or preventive manage-ment for this neurological disorder.

Several histopathological studies have documented that AD ischaracterized by the presence of (a) senile plaques, mainly formedby amyloid beta (Abeta) peptides located extracellularly and (b)neurofibrillary tangles, an altered intracellular arrangement of theTau protein [20,21]. Evidence from genetic and biochemical studiessupport the hypothesis that accumulation of insoluble aggregatescomposed of Abeta peptides constitutes one of the main compo-nents in the pathogenesis and subsequent events of AD [22,23].Abeta peptides (39–43 amino acid polypeptides) are generatedfrom the amyloid precursor protein (APP) [24], a membrane proteinwidely distributed in the brain whose function is still unknown. TheAPP is cleaved by a group of protein-processing complexes calledsecretases [23]. The � and � secretases have been involved in thegeneration of Abeta 1–40 and 1–42 peptides; the latter aggregateseasily and is frequently present in senile plaques and cerebrovas-

sion of this protein. (5) Cu binding to Abeta increases the production of free radicalsby itself and by inhibition of mitochondrial respiratory chain. APP, Amyloid betaprotein precursor; BACE, beta secretase; ROS, reactive oxygen species; NMDAR,ionotropic Glutamate receptor NMDA type; PI3K, phosphoinositol-3-kinase; AKT,protein kinase B; GSK-3, glycogen synthase kinase 3; MAPK, mitogen activatedprotein kinase; MMP, matrix metalloproteinases.

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27–29], especially redox active metals; since it has been suggestedhat these metals could be involved in most events underlying theathogenesis and progression of this neurological disease includingxidative stress and protein aggregation.

.1. Fe homeostasis in AD

Fe is involved in the pathophysiology of AD as suggested byts presence in senile plaques and neurofibrillary tangles in post

ortem brains from AD patients [29]. Fe has been associated withree radical generation through the Fenton reaction, leading to theormation of the highly reactive hydroxyl radical. It is worth men-ioning that the hydroxyl radical not only affects cell moleculesuch as membrane lipids, proteins and nucleic acids but also seemso contribute to Abeta aggregation by promoting covalent bindingetween peptide monomers [30]. The association between Abetand transition metals such as Fe and Cu may also lead to the gen-ration of hydrogen peroxide, exacerbating the oxidative damage31,32].

The role of Fe in this disorder is supported by the studies link-ng hereditary hemochromatosis to AD [33] and the presence of anron responsive element in the untranslated region of the APP gene34]. Additionally, ferritin is also present in senile plaques in brainsrom patients with AD [35]. Supporting an important role for ironn AD, a study carried out by Ding et al. [36] showed positive corre-ation between iron levels in the hippocampus, measured by phasemaging, and the Mini-Mental State Examination of AD patients.

An interesting strategy for AD treatment has been Fe chelation,ince this metal is involved in free radicals generation and thus, inxidative stress. Reports concerning the Fe chelating approach haveeen historically documented [37] and current attempts are look-

ng for molecules not only with metal-binding properties but alsoith the ability to diminish oxidative stress, as will be discussed

ater.

.2. Cu homeostasis in AD

Current evidence suggests that AD development involves anltered Cu homeostasis. On the one hand, some studies supporthe idea that Cu participates in the development of AD as a nox-ous metal. On the other hand, some other findings suggest that ADould be the result of diminished availability of Cu in neurons. Inegard of the former, it should be mentioned that high content ofu has been found in amyloid plaques from AD brains [29]. In theriple transgenic murine model of AD; exposure to Cu in the drink-ng water for three and nine months produced the exacerbation ofoth Abeta and Tau pathologic consequences [38]. Such study sug-ested that Cu may be influencing not only the senile plaque, butlso the neurofibrillary tangles. It should be noted that the Abetasnvolved in the pathogenesis of AD show high affinity for Cu [39].u binding possibly promotes Abeta toxicity through the formationf hydrogen peroxide and the subsequent generation of free radi-als through the Fenton reaction, as has been extensively reportedor Fe [40,41]; this effect may involve a one-electron Cu(II) reduc-ion by Abeta [31,40]. Consequently, a cascade of events related toxidative stress and subsequent neuronal death occurs (Fig. 1). Itas been reported that the Abeta inhibits the cytochrome c oxidaseomplex of the mitochondrial electron transport chain [42] andther studies indicate that this inhibition may be further increasedy the presence of Cu(II) ions, requiring approximately 0.75 molef metal per mole of polypeptide to inhibit cytochrome c oxidase
nd to promote peptide aggregation [43,44]. This effect may be dueot only to the ability of the Abeta-Cu complex to generate hydro-en peroxide but also to the formation of an intermediate reactiveroduct that interacts with cytochrome c oxidase [43], suggestingnother cell damage mechanism elicited by Cu. In glutamatergic
al Interactions 186 (2010) 184–199

neurotransmission Cu is co-released with glutamate and substan-tial amounts of Cu ions, susceptible to bind Abeta (coming from theaction of secretases on APP) can be found in the synaptic space [45],this extracellular binding also enhance Abeta oligomerization andprecipitation and thus the formation of senile plaques (Fig. 1).

The function of APP is still unknown; however, it has been sug-gested that APP-Abeta may act as a Cu carrier system since APPknockout mice showed an increased Cu content in the cortex ascompared to wild-type animals [46]; those findings are comple-mentary to human studies [47,48] and if true, it would explain whycopper deficiency down-regulates APP transcription [49] and theAbeta’s high affinity for copper [39].

On the contrary, evidence supporting a deficiency of Cu in ADis based on findings now discussed. Cu concentration in the cere-brospinal fluid (CSF) from AD patients was inversely correlated toAbeta [50]. Experimentally, Cu has been associated with the upreg-ulation of the Abeta degrading metalloproteinases MMP-2 andMMP-3 in the rodent lung [51,52]; other studies suggest that thismay also occur in brain [53]. Studies in APP-overexpressing ChineseHamster Ovary (CHO) cells showed that increasing Cu concentra-tions reduced Abeta synthesis and thus reduced amyloidogenesis[54]. Those studies showed that Cu acts at different levels: it partic-ipates in APP processing into non-amyloidogenic derivatives whileits deficiency reduces Abeta degradation [55].

Cu deficiency may also influence the activity of Cu-bindingproteins in AD. In this regard, it has been observed a reducedCu/Zn superoxide dismutase (SOD) activity [56] in the CSF from ADpatients when compared to controls and the activity of cytochromec oxidase, another Cu dependent protein, is also reduced in AD [57].Ceruloplasmin (Cp), a multicopper ferroxidase necessary for theoxidation of Fe2+ to Fe3+ and subsequent binding of Fe to transferrin[58], could be an important factor in AD because in this protein con-verge both Cu and Fe homeostasis. However, there are conflictingreports in the literature; Cp content has been significantly increasedin most brain regions of AD patients compared to elderly controls[59]. Whereas, decreased levels were found in the temporal cor-tex [60], probably due to methodological differences. Regarding Cpferroxidase activity, a tendency towards decrease was observed inthe CSF from AD patients [61]. In vitro, it has been observed, thatchelation of about 27% of total Cu in the neuroblastoma cell lineSY5Y produces an appreciable increase in the intracellular Fe level[55], due to the loss of Cp ferroxidase activity.

Serum levels of both Cu and Cp were significantly higher in agroup of AD patients versus controls, according to Squitti et al. [47].The same authors, in a different study [48], could not find an associ-ation between serum Cp bound-Cu and cognitive impairment or theincreased concentration of Cu in CSF. A recent report by our groupshowed a trend towards an increased CSF free-Cu concentrationin AD patients, accompanied by reduced Cu–Zn SOD and ferrox-idase (Cp) activities [56]. The evidence discussed above suggeststhat altered Cu homeostasis exists in AD and that such alterationcan lead to a redox dysequilibrium by altering the functioning ofimportant enzymes like Cu–Zn SOD and Cp. Therapies focused onmetal chelation and recently, on the Cu transport into the centralnervous system, have been tested.

2.3. Metal-related therapies for AD

A trial in AD patients with deferoxamine, an Fe chelator, showeda delayed loss of daily living skills, compared to the group receiv-ing placebo [37]; however, the reduced crossing of deferoxamine
through the blood–brain barrier, due to its molecular size andthe functional groups within its structure, have limited its clinicalapplication.
Fe chelators with several other mechanisms of action have beenassayed in vitro. In neuroblastoma SH-SY5Y cells, the drug M-30

ologic

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long with other congeners (VK-28 and HLA-20), prevented serumeprivation-induced apoptosis; they also stimulated cell differen-iation and neurite growth. In CHO cells stably transfected with thePP gene, M-30 reduced APP expression and increased the soluble

orms of Abeta [61].Some vegetal derivatives have also been tested in AD mod-

ls, because of their antioxidant, anti-inflammatory, metal-bindingnd membrane-crossing characteristics. The green tea flavonoid,pigallocatechin-3-gallate (EGCG) reduced Abeta formation, bothn vitro and in vivo, by modifying APP metabolism leading to solu-le non-amyloidogenic products [62]. Those actions can be due to

ts Fe chelating properties [63]. Curcumin, a polyphenolic deriva-ive of turmeric, reduced Abeta aggregation and the formation ofenile plaques in mice expressing APP [64]. However, this deriva-ive did not lead to a significant effect in a double-blind clinical pilottudy [65]. Blat et al. [66] have recently used a modified octapep-ide (NAPVSIPQ = Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) that inhibitedipid peroxidation and decreased the hydroxyl radical formationossibly through Fe chelation. Deferiprone, another iron chela-or, produced a decrease in iron signals as measured by MRI inhe dentate nuclei of Friedreich ataxia patients and neurologicmprovement was also noted [67]. Deferiprone analogues haveeen covalently attached to nanoparticles as a strategy to increase

ts crossing through the blood–brain barrier. Those nanoparticlereparations were tested in fixed tissue from AD patients and inultured cells; they removed Fe and adsorbed Apolipoprotein E68,69]. Their effect on animal models remains to be determined.

Regarding therapies aimed to restore Cu normal levels in theD brain, it has been observed that Cu chelators also increase theolubilisation of Abeta deposits from post-mortem AD brain tis-ue in vitro [70]. Treatment to AD patients with d-penicillamine, au-chelating compound, reduced oxidative stress; however, thisffect was not reflected in their cognitive decay-rate [71]. Theu chelator pyrrolidine dithiocarbamate prevented the cognitiveeficit and reduced Tau phosphorylation by interfering with thekt/GSK-3� pathway in transgenic mice. Interestingly, pyrrolidineithiocarbamate increased Cu content in the cortex as comparedo wild type or APP/PS1 mice [72]. Then, it is possible thatyrrolidine dithiocarbamate not only chelates Cu, otherwise itould move Cu from locations where Cu is in excess to loca-ions where Cu is needed. This fact could explain why the use ofther Cu chelators resulted in no neurological improvement [71].upporting this hypothesis, Clioquinol (CQ), a metal-binding com-ound that crosses the blood–brain barrier, reduced the numberf senile plaques in the brain of transgenic mice [73], delayedognitive impairment and decreased plasma Abeta levels in ADatients [74]. A mechanistic study using APP-expressing CHOells showed that the complex of CQ with Cu(II) decreased thextracellular Abeta levels by upregulating the matrix metallo-roteinases MMP-2 and MMP-3 that cleave Abeta. The CQ-Cuomplex transports the metal inside the cells [53]. Furthermore,n APP-expressing mice, treatment with CQ alone enhanced mor-ality, whereas co-treatment with Cu reduced it (versus CQ group)nd also increased brain Cu levels [75]. CQ would be a potentialherapy for AD; however, its most important drawback is thatt was implicated in an epidemic of sub-acute myelo-optic neu-opathy in the Japanese population during the 1970s. Anothertrategy aimed to adequately transport Cu into the cell is the usef the complex Glyoxalbis(N(4)-methyl-3-thiosemicarbazonato)-opper(II) (Cu-GTSM), a metal bis(thiosemicarbazone). Treatmentf APP-CHO cells with Cu-GTSM showed that Cu(II) bioavailabil-
ty significantly increased and the levels of secreted Abeta wereeduced in a dose-dependent manner [76]. Further studies showedhat Cu-GTSM increased the copper bioavailability in cultured cellsn about 400%. This compound also enhanced the phosphorylationnd further inhibition of GSK-3�, the kinase involved in the modi-
al Interactions 186 (2010) 184–199 187

fication of Tau protein and the formation of neurofibrillary tangles.Transgenic APP/PS1 animals treated with this compound showedan enhanced performance in the Y maze as compared to those ani-mals without treatment, furthermore, levels of trimeric Abeta werealso reduced in those animals treated with the copper complex [77].

Additionally, a series of Cu-complexed compounds, have alsobeen tested in APP-expressing CHO cells. Those complexes wereable to boost the metal content inside the cells but only those thatreleased the metal were able to increase the degradation of Abetaby activating the PI3K phosphorylation cascade and the expressionof MMPs responsible of the degradation of Abeta [76].

Recent innovations regarding drug design have led to thesynthesis of drugs with acetylcholinesterase activity and Cu/Fechelating properties; those compounds also inhibited Abetaaggregation. Theoretically, the new synthesized molecules mayconstitute potential therapeutic tools, only after completing in vivoand safety studies [78].

2.4. AD: concluding remarks

Cu has shown dual properties in AD. Abeta binds Cu with highaffinity and this union is involved in the generation of free radi-cals and inhibition of mitochondrial function. Cu ions (coming fromdisrupted Cu transport or from physiological release during gluta-matergic transmission) are also involved in the formation of senileplaques by precipitating Abeta oligomers. On the other hand, sub-stantial evidence suggests that low intracellular Cu: (a) is involvedin the biosynthesis of Abeta from APP, (b) limited functioning ofcopper dependent antioxidant enzymes, i.e. SOD and (c) dimin-ished copper dependent ferroxidase CP activity that in the longterm would lead to Fe cell deposition thus increasing oxidativestress. It remains to be determined if current experimental ther-apies in AD that include the transport of Cu into cells are in fact areal alternative. It is worth mentioning that Cu-binding drugs couldbe redistributing the metal from rich-Cu compartments to areaswhere the metal is needed.

3. Parkinson’s disease

PD is the second most prevalent neurodegenerative disorderworldwide [79]. It is mainly characterized by motor disturbancessuch as tremor, rigidity and bradykinesia [80,81], although cogni-tive and behavioural abnormalities have also been reported [82,83].PD occurs following dopaminergic neuronal death within the sub-stantia nigra pars compacta (SNpc) [79–81] but the etiology ofthis selective neurodegeneration is still unknown [84,85], althoughseveral genetic and environmental factors have been implicated[80,85]. Among those factors, occupational exposure to transitionmetals, especially Fe and Cu, has been proposed as a risk factorfor the development of PD [86,87]. Several studies support the roleof brain transition metal accumulation in the pathophysiology ofPD that may be independent on the environmental exposure, sug-gesting that metal homeostasis in PD is altered. The neurotoxicpotential of Fe has been consistently reported while in the case ofCu the evidence is not completely conclusive as will be discussedlater.

3.1. Fe homeostasis in Parkinson’s disease

Although Fe is very important for physiological processes in sev-
eral organs including the brain, its role in the pathophysiology of PDhas been extensively studied and a wide body of evidence showingits neurotoxic effects has been reported [88–90], especially on tyro-sine hydroxylase-immunopositive neurons as demonstrated by Femicroinjection to the substantia nigra (SN) [90].

1 ological Interactions 186 (2010) 184–199

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Fig. 2. The reciprocal modulation of Fe and Cu and its further association withexcitotoxicity in PD. Glutamate increases Fe uptake through a NO-dependent mech-anism involving DMT1 (1). Fe, in turn, may increase glutamate release (2). Excessiveglutamate induces excitotoxicity through a NMDA-mediated mechanism (3). Cu canprotect neurons against Fe overload by competing for transport through DMT1 (4)


Total Fe levels have been found to be increased in the SNpcut not in the cerebellum, caudate nucleus, putamen or cerebralortex from post mortem PD brains [91–94], suggesting that thenderlying mechanisms for Fe accumulation may be specific for theNpc. In contrast, levels of this metal were reduced in the globusallidus compared to control values [92]. It should be noted thaton-significant difference in Fe content has been found in brainissue showing moderate neurodegeneration [94]; thus, it could beonsidered that Fe accumulation in PD might be the consequence ofhe underlying mechanisms of neuronal death since otherwise itsevels should be expected to be increased since the early stages ofhe disorder; thus, some mechanisms may initiate neuronal deatht the early stages of the disorder and lead to Fe accumulation that,n turn, may potentiate oxidative damage.

Interestingly, ferritin-reactive microglia has been found sur-ounding degenerating neurons [91]. Since ferritin is the maine-binding protein, this result suggests that Fe accumulates withinicroglial cells and several hypotheses may be suggested in this

egard. On the one hand, it is possible that microglia release Fe thatould be toxic to the surrounding neurons; on the other hand, Feay accumulate in both neurons and microglia but the former may

e more sensitive to the toxic effect of this metal and thus surviv-ng ferritin-positive microglia may be found in post mortem brainissue surrounding degenerating neurons. The role of microglia inrain Fe accumulation deserves further investigation.

Whatever the cell type responsible for Fe accumulation, the con-ent of this metal is increased in the SNpc in PD and it has beenetected in living patients by neuroimaging methods. Transcranialonography has revealed that the SN in PD patients is hypere-hogenic, most likely due to metal deposits in this region [91,95,96].his hyperechogenicity may be present in up to 90% of PD patients91] and may also be found in healthy subjects, but even in thisase it reflects nigrostriatal dysfunction to some extent, since its associated with decreased [18F]DOPA uptake [91,95,97]. Also,yperechogenicity in healthy elderly subjects is associated withotor alterations such as hypokinesia [91]. SN hyperechogenicity

s most likely due to Fe accumulation since the echogenicity of postortem human brain tissue correlates well with Fe content, but notith that of Cu, magnesium, zinc or calcium [91,97]. Other imagingndings further support Fe accumulation in the SNpc in PD [98,99]nd its role on nigrostriatal dysfunction in this disorder PD.

Brain Fe content increases during normal ageing and it is asso-iated with a reduced motor performance [100]. Fe content in PD isigher than expected by normal ageing and the underlying mech-nism for such accumulation remains to be completely elucidated11] but several studies have shed some light in this regard. Excito-oxicity might be involved in PD and may lead to Fe accumulation.e uptake is enhanced by N-Methyl-D-Aspartate (NMDA) receptorctivation. through nitric oxide (NO) signalling [89]. Both gluta-ate and NO are involved in excitotoxic death which is suggested

o occur in PD (Fig. 2); thus, Fe accumulation in this disorder maye associated with neuronal death through glutamate receptors89]. Further studies support this neurotoxic pathway. Fe chelationeduces NMDA-induced excitotoxicity [89].

NO increases Fe uptake through a transferrin-independentechanism most likely mediated by divalent metal transporter

DMT1) [89]. Furthermore, high NO concentrations are ableo displace Fe from Fe–sulfur centers in some proteins suchs mitochondrial complex II, forming dinitrosyl-Fe complexes101] thus increasing the potentially neurotoxic free-Fe pool. Fe

ay potentiate excitotoxic cell death since glutamate release
fter ischemia/reperfusion is higher in animals fed with a Fe-upplemented diet [88].
It is well known that Cu-proteins Cp and hephaestin oxidize Fe+2

o Fe+3 in order to facilitate iron removal as it has been demon-trated by iron overload and neurodegeneration in the double

and favoring Fe efflux through IREG1 (5). DMT1, divalent metal transporter 1; IREG1,ferroportin; NMDAR, glutamate NMDA receptor; NO, nitric oxide; NOS, nitric oxidesynthase.

knockout mice lacking both Cp and hephaestin [102]. The possi-bile role for these two proteins in PD has been explored [103,104].In a model of PD using 6-hydroxydopamine (6-OHDA) a decreasedexpression of hephaestin was found [103], while mutations of theCp gene have been associated to PD [104]. Therefore, it is possi-ble that iron overload could be in part a consequence of alteredoxidation of Fe, preventing its extrusion.

Recently, upregulation of DMT1 in the SNpc of PD patientsand in the SNpc of mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin known to induce severalfeatures of PD, has been demonstrated [105]. These resultswere confirmed by treating the dopaminergic cell line MES23.5with 1-methyl-4-phenylpyridinium (MPP+), the active, the activemetabolite of MPTP [106]. DMT1 upregulation was correlated toupregulation of DMT1 was correlated to Fe accumulation. Addition-ally, rodents carrying a mutation that impairs DMT1 Fe transportwere partially protected from injury caused by both MPTP and6-OHDA. These evidences point towards a direct involvement ofDMT1 in Fe accumulation and consequently, in the pathophysiol-ogy of PD.

Once Fe is accumulated in PD it could enhance neuronal deaththrough oxidative stress. Fe induces lipid peroxidation [107,108]and increases ROS production by 6-OHDA auto-oxidation [109].Fe also stimulates the formation of intracellular aggregates of �-synuclein and favors oxidative damage [110]. It is known thatautosomal dominant PD is related to mutations in �-synuclein thatenhance aggregation of the protein [111] therefore, those individ-uals with mutations in �-synuclein could be more susceptible tooxidative damage by Fe.

Although Fe accumulation in PD is not explained by ageing itself,ageing modulates Fe neurotoxicity. Adult mice (12–24 months old)fed with Fe during the neonatal period showed reduced striataldopamine content while their young counterparts (2 months old)have unchanged dopamine levels following the same treatment[80,112]. However, although brain Fe accumulation in young ani-mals is not likely to produce neuronal death by itself, early postnatalFe administration potentiates MPTP-induced dopamine depletionduring adulthood [113], suggesting that Fe accumulation in young
animals may lead to neurotoxicity.
As mentioned before, Fe(II) may lead to neuronal damage due tooxidative stress through the Fenton reaction with hydrogen perox-ide (H2O2) [114,115]. The H2O2 supply for this reaction may arise

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rom monoamine oxidase activity and also from Fe-induced oxida-ion of dopamine [79] among other possible sources, leading to thenhancement of this damaging mechanism. Increased glutathioneiosynthesis is observed in survival cells after Fe overload [114]uggesting that oxidative stress is directly involved in Fe neurotox-city.

.2. Cu homeostasis in Parkinson’s disease

Several studies have shown that Cu may lead to both toxicnd protective effects under certain experimental conditions. Toxicffects have been reported for peripheral tissues while its protec-ive effects have been found against certain paradigms of neuronalamage. Since brain Cu content has been reported to be decreased

n PD [92,116], the toxic effects that occur at high concentrationsre not likely to be involved in the pathophysiology of this disor-er while its protective effects are relevant in the case of a possibleu-deficiency in PD.

Multivariate analyses have shown that occupational co-xposure to both Pb and Cu for 20 years or more significantlyncreases the risk for PD (odds ratio 5.0); however, the associationf exposure to Cu only did not reach statistical significance in sometudies [86]. Thus, it remains to be determined if Cu exposure itselfs associated with PD or if it depends on the simultaneous exposureo other risk factors.

Cu has been implicated in the pathophysiology of PD since itsoncentration has been found altered in the brain and CSF fromatients with this disorder [56,117]. In a post mortem study, Cuontent was shown to be significantly higher in the reticular for-ation in PD cases [94]. In contrast, several studies suggest that

rain Cu levels are deficient in PD. Total Cu content is reduced inhe SNpc [92] and the caudate nucleus [59], but not in the cerebel-um, globus pallidus, putamen or the dorsolateral prefrontal cortex94] from PD brains. Regarding Cu content in CSF, while total Cuoncentration is not changed in PD patients compared to controls56,118] free Cu is increased and positively correlated to both dis-ase duration and Unified Parkinson’s Disease Rating Scale motorcores [56]. It is possible that free Cu levels might lead to oxidativetress and neuronal death in PD through the Fenton reaction; also,ree Cu could be increased due to the uncoupling from its bind-ng sites in antioxidant proteins (such as Cp and SOD) leading toxidative stress.

Cu(II), as well as other metals, binds to �-synuclein with dis-ociation constants in the micromolar range (40–500 �M) andnduces oligomerization of this protein when incubated eitherlone [119,120] or in combination with H2O2 [121,122]. Also, Cp-ound Cu leads to ROS-mediated �-synuclein aggregation when

ncubated with H2O2 [123]. However, this effect has been studiedn vitro and is dependent on the experimental conditions tested;n this regard, some studies did not find any effect of Cu(II) (at au:protein ratio of 10:1) on �-synuclein oligomerization and, inontrast, suggest that this cation might inhibit the spontaneousggregation of the protein [124]. Thus, the effect of Cu on �-ynuclein oligomerization in vivo remains to be elucidated.

Cu(II) (0.2–1.0 �M) although is inactive by itself, enhancesysteine autoxidation-induced neurotoxicity [125]. However, Cueficiency could also lead to nigrostriatal dysfunction since ratsed with Cu-deficient diets during gestation and lactation showeduced striatal dopamine content [126]. Furthermore, both acutend chronic Cu(II) administration has shown neuroprotectiveffects against both MPP+ and quinolinic acid neurotoxicities
127–129]. Moreover, in contrast to Fe, Cu chelation is not pro-ective against MPTP injury [130] and even, as in the case ofiethyldithiocarbamate, can enhance neurotoxicity [131].
The neuroprotective effect of Cu may involve the modulationf Fe transport. Cu reduces Fe uptake possibly through neuronal

al Interactions 186 (2010) 184–199 189

DMT1 [115]. Decreased DMT1 expression is associated with neu-ronal survival following Fe overload [132]; thus, an inhibitory effectof Cu on Fe uptake is also expected to be neuroprotective. Bothoral and intracerebroventricular Cu administration are neuropro-tective against dopaminergic degeneration; oral Cu administrationmay lead to this effect by decreasing Fe levels since Cu competeswith Fe for intestinal absorption [115], thus decreasing Fe uptake,and consequently, the brain content of this metal.

Modulation of Fe transport through ferroportin (Ireg-1) mayalso be involved in the neuroprotective effect of Cu since this pro-tein mediates Fe efflux (Fig. 2) in neurons and astrocytes [115,132].Increased ferroportin expression is associated with neuronal sur-vival after Fe overload [115]. Cu-deficient diets reduce ferroportinexpression in the rat liver [133] leading possibly to Fe accumula-tion; in patients with non-alcoholic fatty liver disease, low hepaticCu content is associated with a decreased ferroportin expres-sion, thus contributing to Fe accumulation in those patients [133].According to those studies, Fe accumulation may be the conse-quence of Cu deficiency. As a matter of fact, Fe accumulates inseveral tissues during Cu deficiency [115], supporting this hypoth-esis.

Cu-deficient diets lead to a reduced Cp activity [134]. Cu(II)(20 nM) induces Cp expression in cultured liver cells [135] andchelation of this ion leads to the opposite effect [136]. Cu chelationmay lead to intracellular Fe accumulation by decreasing ferroportinexpression [136]. The underlying mechanism for this effect mostlikely involves Cu-mediated Cp activity, since ferroportin target-ing to the astrocyte plasma membrane is absent in Cp knockoutanimals [136]. This interaction is due to the ferroxidase activity ofCp since this activity at the plasma membrane reduces the extra-cellular Fe(II) concentration leading to an increased expression offerroportin to compensate for the Fe(II) depletion by increasing itsefflux [136].

As an altered metal homeostasis seems to exist also in PD, someattempts aiming to regulate metal levels have been made in orderto treat this disorder.

3.3. Metal-related therapies for Parkinson’s disease

As discussed in Section 3.1, several studies have consistentlyshown that Fe is accumulated in the SNpc of PD patients. Also,a wide body of evidence supporting the neurotoxic potential ofFe overload has been reported [88–90]; however, no therapeuticapproach targeting Fe accumulation in PD has been performed todate. Fe chelation is neuroprotective in animal models [89,137,138]but may not be convenient in the clinical practice, not only due tothe interference with the physiological role of this metal but alsoto the lack of a specific Fe binding and the potential adverse effectsof Fe chelators [1]. Thus, beyond Fe chelation, different attemptsfocusing upstream (Fe intake) or downstream (antioxidant effects)events have been performed. High Fe intake in the diet is a riskfactor for PD [139] possibly by increasing brain Fe concentration.This suggests that dietary Fe restriction may be beneficial in PD ashas been found in experimental models [140]. It is possible that asingle mechanism of action is not sufficient to slow the progres-sion of a complex disorder such as PD. Since not only Fe overload[80,90,112], but also Fe restriction [140], leads to nigrostriatal dys-function it is possible that metal homeostasis, rather than excess ordeficiency, needs to be achieved in PD but this issue awaits furtherinvestigation.

Therapeutic strategies regarding Cu have also been tested. Rojas
et al. [141] administered EGb761, a well-defined mixture of activecompounds extracted from Ginkgo biloba, to MPP+-treated mice.EGb761 pretreatment resulted in the prevention of changes in cop-per levels observed in mice treated only with MPP+. The fact thatcopper homeostasis is returned to normality may contribute to

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he protective effects of EGb761 in this model. Pretreatment withuSO4 to MPP+-treated rats prevented protein nitration, tyrosineydroxylase inactivation as well as the dopamine-depleting effectf MPP+ [128]. Probably, strategies aimed to restore barin Cu levelsan be helpful in PD treatment.

.4. PD: concluding remarks

A central role for Fe accumulation in mesencephalic tissue isbserved in PD, the reason for this effect is still unknown; how-ver, Fe transporters DMT1 and ferroportin seem to be involved.e burden in dopaminergic brain areas takes a major importanceince the catabolic route of dopamine produces hydrogen perox-de that in presence of Fe favors Fenton reactions and excessivexidative stress. The CP ferroxidase activity could play an impor-ant role, since isoform variations and low activity of this enzymeseparately) have been linked to increased nigral echography thatn turn, is related to Fe accumulation. Cu may also influence theontent of Fe in neurons, not only because of the effect elicited byeruloplasmin, but also on iron transporters DMT-1 and ferroportin.ore studies are necessary to explore the relationship between Cu

nd Fe and to propose related-strategies in PD.

. Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative dis-ase of unknown etiology clinically manifested by weakness andasting of the affected muscles with pyramidal signs. ALS is char-

cterized by the progressive loss of motor neurons of the anteriororns in the spinal cord, bulb and cortex [142].

ALS seems to be sporadic in 90% of all cases, while familialmyotrophic lateral sclerosis (FALS) showing dominant autosomalnheritance, represents 10% [143]. Over 110 FALS-linked mutationshroughout the SOD1 gene are related to approximately 20% ofhe FALS cases [144,145]. In FALS, SOD1 acquires a toxic functions demonstrated by transgenic models showing that mice overex-ressing the human mutant enzyme G93A exhibit features of ALS146] while those lacking the enzyme do not develop the disease147].

Cytoplasmic aggregates have been found in motor neurons fromporadic and FALS patients and from transgenic mice models of ALS.hose aggregates include Bunina bodies [148], skein-like inclusions149] and Lewy body-like inclusions [150]. Interestingly, Lewyody-like inclusions are immunoreactive for SOD1 [151] and theresence of this protein in several enzyme mutant aggregates cor-elates with disease onset and progression [152].

Superoxide dismutases are the major antioxidant enzymesnvolved in free radical scavenging. SOD1, SOD2 and SOD3, cat-lyze the dismutation of superoxide anions yielding H2O2 and O2,reventing intracellular damage [153]. Human SOD1 is a 32 kDaomodimeric metalloenzyme containing one Cu and one Zn ioner subunit [145]. The Cu ion bound to the SOD1 active site has aatalytic function, while the Zn ion maintains the enzyme structure154]. The association between SOD1 mutations and FALS suggestshat oxidative injury is involved in this disorder [155].

.1. Fe homeostasis in amyotrophic lateral sclerosis

Increased spinal cord Fe levels reported in ALS [156,157] areossibly involved in oxidative damage through the Fenton reac-ion. It has been suggested that Fe accumulation may be due to
ncreased uptake of this metal [11] since lactoferrin is increased inLS affected motoneurons [158]. Ferritin is upregulated in SOD1-93A mice just prior to end-stage disease, suggesting an increasede deposition [159]. Moreover, in ALS patients, CSF ferric reduc-ng ability is decreased, while the content of oxidized proteins is

increased both in CSF and plasma [142]. SOD activity modulatesthe levels of TfRs, ferritin and Ireg-1 [153].

The expression of proteins associated with iron homeostasis,DMT1, TfR1, the iron exporter Fpn and Cp has been studied in atransgenic mice model of ALS; a caudal-to-rostral gradient in themRNA levels of these proteins, with the highest levels rostrally inthe cervical region, were found [160]. Such a distribution correlateswith the caudal-to-rostral progression of the disease in SOD1-G37Rtransgenic mice.

Interestingly, Mizuno et al. [161] found that transferrin colocal-izes with Bunina bodies in the spinal cord of ALS patients; therefore,transferrin possibly interacts with cystatin C since they are the onlyknown proteins in Bunina bodies [162].

Another evidence supporting the involvement of Fe in this disor-der is that the prevalence of HFE (hemochromatosis gene) mutationin ALS patients is the second most frequent in this disease [163]. HFEinteracts with the TfR to sense Fe levels [164]; its polymorphismshave been associated with hereditary hemochromatosis [165], agenetic disorder resulting in free Fe accumulation in parenchymaltissues. Moreover, HFE mutations are associated with a decreasedexpression of SOD1, �-tubulin and �-actin [163]. Therefore, it ispossible that HFE polymorphisms in ALS are associated with analtered Fe homeostasis and, consequently, with oxidative damagein this disease [166].

4.2. Cu homeostasis in amyotrophic lateral sclerosis

As SOD1 contains Cu and Zn, altered levels of those metals havebeen associated with ALS pathology. In patients with this disor-der, Cu levels have been reported in CSF and serum only, and theyvary from low [167] to unchanged when compared to controls [56].However, in transgenic models of FALS, Cu levels are increased inthe spinal cord of rats [168] and mice [169–171].

Changes in spinal cord Cu content could be explained, at leastin part, by the downregulation of atp7b gene (encoding a Cu-transporting ATPase) in SOD1 transgenic mice [159]; however,Jonsson et al. [172] suggested that the deficient Cu-coupling toSOD1 is not due to a general decrease in tissue Cu uptake, but to analtered process in the protein folding.

Altered Zn and Cu levels could be the consequence of struc-tural changes in SOD1. The FALS SOD1 proteins can be divided intotwo groups according to their metal content [173] and the posi-tion of the specific mutation. Metal content in wild-type-like (WTL)mutant SOD is nearly identical to that found in the wild-type pro-tein, whereas mutations at the metal-binding region (MBR) or atthe electrostatic and Zn loop elements [174] lead to a deficiency inZn and Cu content [173]. WTL-SOD1 mutants show high reactivitywith hydrogen peroxide and produce site-specific oxidative dam-age to the MBR, compromising metal binding, while MBR mutantsappear to aggregate with no further modification [174,175]. Hence,the aggregation of both types of mutants may involve metal uncou-pling.

An increasing body of evidence suggests that SOD1 stability isdependent on its metal-binding state. Some hypotheses hold thatthe balance between normal and toxic SOD1 functioning dependson Zn binding at the active site of the enzyme [176] (Fig. 3);experimental models have shown that in the absence of Zn thecatalytic reaction of SOD1 runs backwards, producing ROS [177].SOD1 proteins that have been oxidatively inactivated by reactionwith hydrogen peroxide lose their affinity for Cu and consequentlythey are more likely to aggregate than the undamaged protein
[178]. It has been observed that even wild-type human SOD1, inits metal-free state, may form large, stable, soluble, amyloid-likeprotein oligomers under relatively mild conditions, although theintrasubunit disulfide bond remains intact, suggesting that thegain of a toxic SOD1 function in ALS may be related to the inabil-

S. Rivera-Mancía et al. / Chemico-Biologic

Fig. 3. The role of SOD metal uncoupling in ALS. SOD mutations can be both MBR-mutations (1) or WTL-mutations (2). MBR-mutant SOD has an altered metal content,while WTL-mutant SOD generally preserves its normal metal content. WTL-mutantSOD is susceptible to oxidative damage compromising metal binding (3). Therefore,both types of mutations can conduce to alterations in SOD structure (4), involvingprotein aggregation (5), gain of toxic function, oxidative damage and apoptosis. TheRepS

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OS generated by dysfunctional SOD can potentiate damage to MBR (6). Cu deliv-red from SOD could be implicated in apoptosis (7). Additionally, Cu and Fe canromote ROS generation through Fenton reaction (8). MBR, metal-binding region;OD1, superoxide dismutase 1; WTL, wild-type-like; ROS, reactive oxygen species.

ty of this protein to achieve or to maintain the metallated state145,179]. The same holds true for ALS mutants that are completelynfolded in the metal-free state [180]. In fact, it has been observedhat Zn binding in ALS mutants can lead to a complete SOD1 fold-ng, reducing oligomeric fractions [180,181]. Metal-free WT andLS-associated SOD1 mutants form disulfide-linked oligomers onlyhen both Cys6 and Cys111 are present [145,182]. It is possible

hat the lack of metal ions distorts SOD1 structure, exposing theys residues and promoting protein aggregation [154].

The loss of Cu and Zn from SOD1 also facilitates the reduction ofhe intrasubunit disulfide bond between Cys57 at the Zn loop andys146 at the �-barrel, thus leading to the dissociation of SOD1ubunits, a fact that greatly increases the formation of insolubleggregates [183,184].

The loss of Zn(II) in turn alters Cu(II) coordination through ahared histidine ligand [177]. In vitro experiments have shown thathe Cu(II) ion at the active site can react with hydrogen perox-de, leading to the oxidation of the Cu(II)-coordinating histidineesidues and the inactivation of SOD1, thus promoting enzymenstability [185]. Zn uncoupling alters human SOD structure evenore than any ALS mutation that has been crystallographically

haracterized, producing the opening of the 4 Å wide channel thatormally avoids small molecules to access the catalytic Cu [186]. Itas been hypothesized that when the Zn(II) ion is unbound to SOD1,Cu ion undergoes a one-electron reaction with molecular oxygen

o form superoxide anion, that further reacts with NO forming per-xynitrite [177]. This pro-oxidant function promotes inactivationf the mutant enzymes, which may also lead to Cu ion release fromhe inactivated protein [187]. It has also been suggested that Znoss from wild-type SOD could be involved in 98% of ALS patients

ithout SOD mutations [186].It has been reported that a FALS-linked SOD1 mutant, H46R,

bnormally binds Cu at a cysteine residue (Cys111) outside thective site [188]; that residue is important to maintain protein sta-ility [189]. As mentioned above, mutant SOD1 exhibits a decreasedffinity for Zn(II) and an increased affinity for Cu(II), the last one

al Interactions 186 (2010) 184–199 191

probably mediated by the Cys111 residue [189]; this incorrectlycoordinated Cu can be highly redox-active and therefore potentiallytoxic. This could lead to a similar effect as that of Cp, which becomespro-oxidant when Cu is abnormally bound outside its active site[190].

Another study supporting the role for Cu in ALS is that per-formed by Kiaei et al. [191]; Cu deficiency induced by the Mobrallele (inhibiting the activity of an ATPase that transports Cu(II)across the intestinal lumen, as it occurs in Menkes disease) in a micemodel of ALS. In that study, a slight increase in the life span of thedouble transgenic mice was found compared with that of the micecarrying only the SOD1-G86R mutation and treated orally with theCu chelator d-penicillamine. It is noteworthy that mutant animalsfor the two pathogenic mutations (Cu depletion plus mutant SOD1)lived significantly longer than the single SOD1 mutant mice. Then,despite mutant SOD can strongly bind Cu, its depletion could bebeneficial in ALS.

Cu has also been implicated in apoptosis. Either Zn-deficientwild-type or mutated SOD initiate apoptosis in cultured motorneurons even in the presence of brain-derived neurotrophic fac-tor; NO-dependent mechanisms are involved [177]. Interestingly, ithas been proposed that Cu activates the Fas apoptotic pathway [2].Cu accumulation induces conformational changes in the X-linkedinhibitor of apoptosis protein that, in turn, plays an important rolein intracellular Cu homeostasis [192], leading to its degradationand decreasing its ability to inhibit caspase activity [193]. Accord-ingly, Cu liberated from Zn deficient SOD could potentially initiateapoptosis (Fig. 3).

SOD1 localization has been related to the enzyme-bindingmetals, while partially or metal-free SOD1 is inserted into the mito-chondria, the holoenzyme is not. Interestingly, in ALS patients andtransgenic mice, the mutant protein is encountered in mitochon-dria [194,195], this effect could be related to the metallated state ofthe enzyme since Okado-Matsumoto and Fridovich [196] reportedthat in mouse neuroblastoma N2A cells, the entry of both wild-typeand mutant SOD1 into the mitochondria depends on its metal-coupling state.

4.3. Metal-related therapies for amyotrophic lateral sclerosis

Therapeutic agents and strategies that reduce the transgenic ALSmice pathology extend their survival for a few days only. Antibioticsof the �-lactam type have been proposed as a treatment since theyare also metal chelators [197]. Administration of the Cu chelatorsDP-109, DP-460 [198], penicillamine [199], N-acetylcysteine [200]and trientine [201–203] have been effective in delaying the dis-ease onset, improving motor performance and slowing the diseaseprogression, in ALS mouse models. Treatment with the Cu chela-tor diethyldithiocarbamate reduced hydroxyl radical production[204] and increased cell survival in in vitro models of FALS [205].Recently, in a transgenic model of ALS Tokuda et al. [171] found thatammonium tetrathiomolybdate (TTM), a Cu chelator used for thetreatment of Wilson’s disease, led to delayed disease onset, longersurvival and slower progression than that of other agents testedbefore, besides restoring Cu levels. Tokuda et al. [171] suggestedthat the removal of the Cu ion bound to Cys111 in mutant SOD1 mayunderlie the effect of TTM. An advantage of TTM is that it chelatesboth intracellular and extracellular Cu ions, whereas other agentsliked-penicillamine and trientine remove only extracellular free Cu[206]. This fact suggests that it is necessary that chelating therapiesfor ALS should be aimed to remove intracellular Cu deposits.

isonicotinoyl hydrazone, a lipophilic iron chelator to transgenicSOD1-G37R mice increased animals life span by 5 weeks. This drugalso helped to preserve neurons and diminished the number of ironcontaining cells without signs of anemia [160].

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.4. ALS: concluding remarks

ALS is characterized by the malfunction of Cu–Zn SOD; mis-olding of the protein, as well as metal-binding alterations aremplicated in this effect. The diminished antioxidant capacity of

otor cell is further aggravated by the SOD1 gain of toxic function,n which Cu bound to the protein plays a central role. Free Cu ionsre also suspected to participate in the cascade of events that endith cell death. Additionally, involvement of SOD in regulating ironroteins plays an important role in Fe accumulation, complicatingxidative stress. The strategy of combining antioxidants and metalhelation may have some potential, especially Cu chelators to with-raw misplaced Cu in the enzyme as well as intra- and extracellularree ions.

. Huntington’s disease

Huntington’s disease (HD) is an autosomal dominantly inheritedeurodegenerative disorder characterized by progressive motor,ognitive and psychiatric deterioration [207]. It is caused by thexpansion of an unstable CAG trinucleotide repeat within the firstxon of the IT-15 gene encoding huntingtin (Htt) protein [208,209].he function of Htt protein has not been completely elucidated;owever, it is possibly involved in endocytosis, vesicular trafficking210], embryonic development [211] and transcriptional regula-ion [212]. The CAG repeat in Htt shows between 10 and 29 copiesn healthy subjects and it is expanded to 36–121 in HD [213]. TheAG repeat yields a polyglutamine stretch within the protein [214].he mutant Htt is widely distributed in most brain regions as wells in peripheral tissues [215] and acquires an unusual conforma-ion, which is hypothesized to produce cell toxicity. Additionally,ltered metal homeostasis has been implicated in HD pathology12,208,216].

Neuronal loss and brain atrophy in HD patients occur mainlyn the caudate and putamen [59], although they may also occur inther regions such as the cerebral cortex, thalamus, globus pallidus,erebellum as well as in white matter tracts [217,218].

.1. Fe homeostasis in Huntington’s disease

Fe accumulation has been reported in the basal ganglia of HDatients [12,216]. Dexter et al. [12] measured post-mortem metal

evels in brain tissue from HD patients and found that total Fe wasncreased in the putamen and caudate nuclei (44% and 56% overontrols respectively), the same brain areas also showed exten-ive pathological disturbances, as a consequence of the disease.n the same study, ferritin levels were unchanged between HDatients and control subjects in all of the brain regions exam-

ned. However, other authors have found increased ferritin levelsn HD brains [13,219], those discrepancies may be due to exper-mental issues. Also, increased Cp levels in HD brains [59] andeduced CSF Cp ferroxidase activity [56] have been reported. Thosendings suggest generalized disruption of Fe homeostasis thatay be due, at least in part, to functional changes in Htt, a phe-

omenon involved in the regulation of the Fe pathway. In turn, Httxpression may be influenced by Fe, as suggested by the studieshowing its upregulation in the presence of the Fe chelator defer-xamine [211]. In this regard, the loss of wild-type Htt [220,221]nd its altered function as observed in mutant Htt, may increaserain free Fe levels [13]; such an effect, may be toxic through the
enton reaction, leading to free radical production, lipid peroxi-ation [56,222], DNA and protein damage and finally, cell death13].
Other possible mechanism involving Fe homeostasis is theutant Htt-mediated stimulation of the lysosomal autophagy


and proteosome systems that, under normal conditions, quicklydegrade ferritin following its Fe-mediated oxidation [13,223,224].Ferritin plays an important role in Fe homeostasis by seques-tering this metal; in turn, Fe levels regulate ferritin expression,which increases with Fe accumulation [225,226]. Simmons etal. [13] analyzed the specific localization of ferritin in thebrain from transgenic R6/2 mice and HD patients; they foundthat ferritin was predominantly increased in microglia; thosecells appeared dystrophic, suggesting that they may be dys-functional and contribute to HD progression. The early increasein microglial ferritin in the R6/2 mice carrying the Htt muta-tion occurs when nuclear inclusions first appear [13,227–229],possibly implying a direct link between ferritin and nuclear inclu-sions.

Oligodendroglia is also possibly involved in HD patho-physiology, as myelination impairment (reviewed in [215])and increased oligodendroglial density have been found inthe brain of HD patients [230]. Differentiation and prolifera-tion of those cells is dependent on Fe stores [231]. It hasbeen hypothesized that elevated oligodendrocyte ferritin levelscould be an attempt to accumulate Fe to support myelination[215].

It is also possible that increased total Fe content involves analtered compartmentalization. In this regard, Lumsden et al. [232],using zebrafish embryos, found that Htt knockdown led to cellu-lar Fe deficiency despite of the availability of this metal. Increasedlevels of TfR1 transcripts were observed in Htt-deficient zebrafish.Htt appears to act downstream of the TfR-mediated Fe endocyto-sis, thus implicating Htt in Fe release from endocytic compartmentsinto the cytosol [232].

On the other hand, the activities of many Fe-dependentenzymes are decreased in HD patients; those include aconitaseand mitochondrial complexes I–IV [233,234], which are impor-tant for energy metabolism. The most consistent finding in HDis a decreased activity of mitochondrial complexes II, III and IV[233,234]. It has been reported that aconitase, a Fe–sulfur (Fe–S)containing enzyme important for the tricarboxylic acid cycle andFe homeostasis [235,236], as well as complexes II and III, are sus-ceptible to inhibition by ROS [237,238] reactive. Decreased activityof those enzymes, as observed in HD, could lead to a self-amplifyingcycle of respiratory chain inhibition and free radical generation[239]. Then, high Fe levels in HD brain could be indirectly dis-rupting the energetic metabolism by free radicals generation. Ithas been proposed that free radicals damage [4Fe–4S] centers,inactivating several enzymes, releasing their catalytic Fe ions andincreasing oxidative injury through the Fenton reaction [240]. Itshould be noted that altered activities of complexes II and III havebeen associated with basal ganglia degeneration [233], as occurs inHD.

Compromised function of the electron transport chain leadsto reduced ATP levels and consequently, to the failure of severalATP-dependent ion pumps. Thus, membrane repolarization will beaffected, releasing the voltage-gated Mg+2 block of the NMDA chan-nel and allowing its activation, even at basal glutamate levels [241].As caudate and putamen nuclei are Fe-rich areas and receive exci-tatory inputs, a synergic toxic effect between Fe and glutamate maybe suggested to occur [11].

Consistent with the damage to mitochondrial respiratory com-plexes, increased lactate concentrations have been reported in thebasal ganglia and occipital cortex [242,243]. Although it seems thatdamage to oxidative metabolism involves Fe dysregulation to a
great extent, it may also involve other mechanisms since reducedlactate dehydrogenase activity has also been reported in the brain ofR6/2 mice following Cu accumulation [208]. Increased lactate con-centration may decrease pH contributing to Fe release from ferritinstores [244].

S. Rivera-Mancía et al. / Chemico-Biologic

Fig. 4. Fe and Cu in Huntington’s disease. Altered Cu homeostasis could disrupthuntingtin structure and function (1). Huntingtin modifications, in turn, lead to anaaa(

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ltered Fe homeostasis (2), conducing to Fe accumulation. Increased Fe levels lead tocascade of events through the Fenton reaction (3), the generation of free radicals (4)nd finally to neurodegeneration. Cu could also be participating in Fenton reaction5).

.2. Cu homeostasis in Huntington’s disease

Both increased [12] and decreased [59] brain Cu levels haveeen found in HD patients, compared to controls. Recently,ur group found that CSF free Cu concentration is associatedith the clinical stage and the time after onset in HD patients

56].Consistent with the interaction between Cu and the Abeta [40],

ox et al. [208] found that this metal promotes Htt aggregationFig. 4) and interacts with histidine (His) residues in the N-terminusf the protein. Moreover, they proposed that reduced lactate dehy-rogenase activity in HD is due, at least in part, to Cu-mediatednzymatic inhibition possibly leading to neurodegeneration. Moretudies are needed regarding the Cu role in HD.

.3. Metal-related therapies for Huntington’s disease

Even though several attempts have been made, there is no effec-
ive treatment for HD. A possible alternative could be focused on
etals. Since Fe accumulation leads to oxidative stress it has beenuggested that Fe chelators could be beneficial in this disorder. Fir-aus et al. [245] reported that pre-treatment with deferoxamineo COS-7 cells transiently transfected with a Htt mutant vector

able 1ummary of some metal transporters involved in neurodegenerative diseases.

Disease Transporter/metal Model

AD DMT-1/Cu, Fe Human postmortem brain, double-transgenic APP/PS1mice, SH-SY5Y cells expressing human APPsw

TfR Human postmortem brain

PD DMT-1/Fe MES 23.5 cells exposed to MPP+/C6 cells exposed to6-OHDAPD patients/Mice exposed to MPTP

TfR/Fe Cerebellar granule neuron primary culture/humanneuroblastoma cells (SH-SY5Y exposed to MPP+)

ALS DMT-1/Fe SOD1-G37R transgenic mice

TfR/Fe SOD1-G37R transgenic mice

Human U373 glioblastoma cell line expressing wild-tyor mutant SOD1 G93A

ATP7B/Cu SOD1-G93A mice

al Interactions 186 (2010) 184–199 193

showed decreased inclusions body size, suggesting a role for Fein the formation of those aggregates. However, Htt is upregulatedin embryonic stem cells (ESC) following Fe chelation with defer-oxamine, leading to nuclear and perinuclear abnormalities in bothESC and STHdh+/Hdh+ striatal cells [211].

CQ reduced polyglutamine expanded levels in vitro and reducedthe pathology and behavioural abnormalities of R6/2 transgenicmice, but it is not known if those effects were due to metal chelationor to other mechanisms [246], although it could be suggested thatthe effect of CQ may involve Cu(II) binding in a 1:2 metal:ligandstoichiometry [247]. Furthermore, it is possible as in AD [53] thatCQ moves Cu from sites where it accumulates to other sites whereit is needed.

EGCG chelates Cu and modulates early events in Htt misfold-ing. It reduced toxicity in a Drosophila model of HD, probably byscavenging free radicals or chelating metal ions [248].

5.4. HD: concluding remarks

Htt mutant expression in HD has been linked to some eventsthat produce Fe accumulation in basal ganglia, thus this metal ispresumably involved in the development of HD. In fact, mutantHtt and Fe are engaged in mechanisms that suggest that onefavors the accumulation of the other causing neurodegeneration.As in the others neurodegenerative diseases the disruption inFe homeostasis, the free radicals as well as protein precipitationare involved. Cu role for this disease is still less clear than thatof Fe and deserves future investigation. Iron chelation could bean interesting approach in transgenic rodent models of the dis-ease.

6. Conclusions

All of the evidence discussed above suggests that disturbancesof metal functioning, regulation and distribution are likely to occur.Mechanisms of damage elicited by Cu and Fe common to AD, PD,ALS and HD include: (a) free radical production, (b) protein aggre-gation and (c) metal transport alteration. Although there are somestudies regarding the role of metal transporters (Table 1) in neu-
rodegenenerative diseases, this is a growing study field, havingthe possibility of studying novel therapeutic strategies, since metaltransporters are involved in brain metal distribution, intracellularlocalization as well as disposal from brain. It is possible that thefinal pictures of metal status in neurodegenerative diseases obeys
Comments References

Fe and Cu accumulation in Abeta plaques. Colocalization ofDMT-1 and Abeta

[249]

Decreased TfR in some cortical regions and hippocampus [250]

Increased DMT-1 expression. Increased Fe influx [251,252]

Increased DMT-1 expression in ventral mesencephalon.Increased DMT-1 expression in SNpc from PD patients. Feaccumulation

[105]

Increased TfR expression [138,253]

Caudal-to-rostral gradient of mRNA expression in thespinal cord. Increased Fe uptake

[160]

Caudal-to-rostral gradient of mRNA expression in thespinal cord. Increased Fe uptake

[160]

pe TfR is upregulated in a dose dependent manner by SOD1(wild-type or mutant G93A) activity. Alteration in Feregulation

[153]

Reduced ATP7B transcripts. Downregulation of Cutransport into the secretory pathway

[159]

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o altered compartamentalization of metals and thus we observehe sum of disturbances caused by the disease and by tissue com-ensative actions.

Detailed studies on the links between altered metal transportnd neurodegeneration will be helpful to facilitate the search forffective therapeutic strategies to avoid damage caused by metalyshomeostasis.

onflict of interest statement

The authors declare that there are no conflicts of interest.

cknowledgements

S Montes, I Pérez-Neri and C Ríos receive grants from CONA-yT (51541, 83521 and 47425, respectively). Rivera-Mancía S andristán-López L receive fellowships from CONACyT (203330 and07021, respectively).

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The transition metals copper and iron in neurodegenerative diseases

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