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Contents lists available at ScienceDirect

Journal of Trace Elements in Medicine and Biology

jou rnal homepage: www.elsevier.de/jtemb

10th NTES Symposium

Review

The neurotoxicity of iron, copper and manganese in Parkinson’s and

Wilson’s diseases

a,b,∗ c,d e f

Petr Dusek , Per M. Roos , Tomasz Litwin , Susanne A. Schneider ,

g h

Trond Peder Flaten , Jan Aaseth

a

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague,

1st Faculty of Medicine and General University Hospital in Prague, Czech Republic

b

Institute of Neuroradiology, University Medicine Göttingen, Göttingen, Germany

c

Department of Neurology, Division of Clinical Neurophysiology, Oslo University Hospital, Oslo, Norway

d

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

e

2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland

f

Neurology Department, University of Kiel, Kiel, Germany

g

Department of Chemistry, Norwegian University of Science and Technology, Trondheim, Norway

h

Department of Medicine, Innlandet Hospital Trust, Kongsvinger Hospital Division, Kongsvinger, Norway

a r t i c l e i n f o a b s t r a c t

Article history: Impaired cellular homeostasis of metals, particularly of Cu, Fe and Mn may trigger neurodegeneration

Received 31 January 2014

through various mechanisms, notably induction of oxidative stress, promotion of ␣-synuclein aggrega-

Accepted 22 May 2014

tion and fibril formation, activation of microglial cells leading to inflammation and impaired production

of metalloproteins. In this article we review available studies concerning Fe, Cu and Mn in Parkinson’s

Keywords:

disease and Wilson’s disease. In Parkinson’s disease local dysregulation of iron metabolism in the subs-

Iron

tantia nigra (SN) seems to be related to neurodegeneration with an increase in SN iron concentration,

Copper

accompanied by decreased SN Cu and ceruloplasmin concentrations and increased free Cu concentrations

Manganese

and decreased ferroxidase activity in the cerebrospinal fluid. Available data in Wilson’s disease suggest

Parkinson’s disease

that substantial increases in CNS Cu concentrations persist for a long time during chelating treatment

Wilson’s disease

Chelating agents and that local accumulation of Fe in certain brain nuclei may occur during the course of the disease.

Consequences for chelating treatment strategies are discussed.

© 2014 Elsevier GmbH. All rights reserved.

Contents

Introduction ...... 00

Parkinson’s disease (PD) ...... 00

Environmental exposure...... 00

Animal models ...... 00

Dysregulation of brain metal homeostasis ...... 00

Wilson’s disease (WD) ...... 00

Local dysregulation of metal homeostasis...... 00

Animal models ...... 00

Concluding remarks ...... 00

Conflict of interest ...... 00

Acknowledgments ...... 00

References ...... 00

∗

Corresponding author at: Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University

Hospital in Prague, Katerinska 30, 120 00 Praha 2, Czech Republic. Tel.: +420 224 965 528.

E-mail addresses: [email protected], [email protected] (P. Dusek).

http://dx.doi.org/10.1016/j.jtemb.2014.05.007

0946-672X/© 2014 Elsevier GmbH. All rights reserved.

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Introduction Parkinson’s disease (PD)

Impaired cellular homeostasis of metals may initiate neurode- Accumulation of several metals, including Fe, Cu and Mn in subs-

generation through various mechanisms. Of these, oxidative stress tantia nigra (SN) has been suggested to play a causative role in the

induced by the formation of free radicals is the best established [1]. pathophysiology of PD [34]. Metal related PD hypotheses are based

Other possible mechanisms are impaired production of metallopro- on:

teins [2,3], activation of microglial cells leading to inflammation [4]

and promotion of aggregation and fibril formation of ␣-synuclein, (1) Epidemiological studies assessing the relationship between

a highly conserved protein with unknown function. This protein environmental exposure to metals and the risk of PD.

is the major constituent of Lewy bodies found as intracytoplas- (2) Clinical observations that disorders with brain metal accu-

matic inclusions in Parkinson’s disease (PD) neurons [5]. Recent mulation such as WD, manganism or the syndromes of

in vitro studies have shown that mutant ␣-synuclein interacts with neurodegeneration with brain iron accumulation (NBIA) may

metals and that iron (Fe) and copper (Cu) seem to aggravate the manifest with parkinsonism.

toxicity caused by the ␣-synuclein [6,7]. It has been suggested that (3) Animal studies examining exposure to high levels of metals and

␣

-synuclein is a Cu binding protein acting as a cellular ferrireduc- the effects of chelation treatment.

tase [8,9]. Lewy bodies contain reactive iron along with aggregated (4) Measurements of metal concentrations and metal regulatory

proteins and oxidized lipid material [10]. protein expression in post-mortem brain tissue samples.

Our knowledge regarding cellular metal homeostasis has (5) Measurements of metal concentrations and metal regulatory

improved substantially over the last years. Several proteins proteins in the CSF.

involved in cellular import, export, trafficking and storage of Fe, Cu

and manganese (Mn) have been identified [11–13]. Among those, Several of these empirical observations are discussed in the fol-

two novel Mn carriers involved in intracellular Mn transport into lowing sections.

lysosomes and Golgi, ATP13A2 and SLC30A10 respectively, have

been found. Other recent findings include roles of the copper trans- Environmental exposure

porter protein 1 (CTR1) in Cu uptake, of Cu chaperones in synthesis

of specific cuproproteins, and of ceruloplasmin in cellular Fe export Effects of Fe and Cu exposure have been sparsely studied and

[14]. Mechanisms of metal transport across the blood–brain bar- a large environmental survey lent little support for an association

rier (BBB) and the blood–cerebrospinal fluid barrier (BCB) have between environmental exposure to Fe or Cu and PD [35]. How-

been thoroughly investigated [11,15,16]. While the brain seems ever, combined exposure to Cu and Fe [36] or Mn and Fe [37]

to be protected against high plasma Fe concentrations as docu- lasting for two to three decades have been reported to significantly

mented in hereditary hemochromatosis [17], this is apparently not increase the risk of PD. Also, toxic effects of Mn have been exten-

true for Mn and Cu. Thus, increased plasma Cu and Mn concen- sively studied [38,39] and excessive Mn intake leads to a specific

trations may lead to brain deposits and CNS damage [18]. It was condition with motor, cognitive and psychiatric symptoms known

recently suggested that Mn enters the CNS predominantly through as manganism, with many similarities to PD. Manganism has been

the BCB and that high Mn concentration impairs the integrity of described largely in workers in mining, welding and smelting

this barrier [19]. There is ongoing research on the roles of Mn industries and in battery factories, but has also been reported in

species and their transporter molecules in brain Mn influx; Mn- communities using drinking water with high Mn concentrations.

citrate was suggested as the species with the highest influx rate Manganism may also arise from intravenous Mn intake, as in long-

[20], and is presumably also the major Mn species in the CSF [21,22]. term parenteral nutrition or in methcathinon (ephedron) abusers

This is in contrast to Fe and Cu which are present in CSF mainly as who use potassium permanganate for the synthesis of the drug [12].

high molecular weight species [18]. Mn and Fe share the trans- Similar clinical symptoms as in manganism have been described

port pathway using the transferrin receptor (TfR) [23,24] and it in end-stage liver diseases and due to mutations in the Mn trans-

has been suggested that Fe deficit may increase brain accumu- porter gene SLC30A10 associated with insufficient biliary excretion

lation of Mn [25,26]. Some authors argue that Fe deficiency may of Mn [40]. Clinical symptoms, neuroimaging findings, pathological

lead to divalent metal transporter 1 (DMT1) upregulation leading examination [41] and lack of response to dopaminergic drugs [42]

to increased Mn uptake [27,28]. There is however controversy to suggest that manganism is not caused by dysfunction of dopami-

what extent the DMT1 is involved in Mn transport [16,29]. Interest- nergic neurons in the SN and that it is pathophysiologically different

ingly, DMT1 is supposedly implicated in Mn uptake by the olfactory from idiopathic PD. It has been suggested that chronic Mn expo-

tract which is another possible route for brain Mn accumulation sure in doses insufficient to induce manganism may be toxic to

[30]. In addition to Fe and Mn interdependencies, interactions the SN rather than the globus pallidus (GP) and can increase the

between Fe and Cu [31] as well as between Fe and calcium [32] risk of developing idiopathic PD [43]. Several epidemiological stud-

metabolism have been reported. Comprehensive discussions of Mn, ies have found an association between Mn exposure and risk of

Fe and Cu transport across BBB and BCB can be found in recent idiopathic PD [36,37,44–49], however other studies do not sup-

reviews [11,15,16,33]. port such an association [35,50,51]. Some reviews [52,53] and one

Despite these advances, it is still unclear to what extent impaired meta-analysis [54] concluded that available data argue against a

metal metabolism affects the pathophysiology of particular neu- relationship between Mn exposure and PD. The latter analysis used

rodegenerative disorders. The aim of this article is to review current strict inclusion criteria leading to exclusion of all studies favor-

literature covering association between metal dyshomeostasis and ing the role of Mn in PD pathophysiology and the topic is still

neurodegeneration, particularly studies measuring concentrations subject to debate. Efforts to establish a firm conclusion are partly

of Fe, Cu and Mn in the cerebrospinal fluid (CSF) or brain tis- hampered by difficulties in differentiating between idiopathic PD

sues of patients with PD and Wilson’s disease (WD) as well as and manganism-related atypical parkinsonism in large scale epi-

studies examining the pathophysiology of metal abnormalities. PD demiological studies [55]. Several factors may increase individual

is a common neurodegenerative disorder with largely unknown susceptibility to PD-related Mn toxicity, e.g. age, ATP13A2 muta-

pathophysiology, while WD is a rare disorder with well described tions, liver dysfunction or iron deficiency [12]. Epidemiological

pathophysiology involving Cu toxicosis where established che- studies of the relationship between Mn exposure and PD should

lating therapy exists. take these factors into account [43].

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Animal models The interval between death and tissue freezing or fixation is also

an important factor influencing the extent of lytic changes that

A selective dopaminergic loss has been produced by intranigral might also alter tissue metal composition. Since procedures used

Fe infusion in healthy mice [56,57], and also by repeated intraperi- to avoid contamination [95,96] are either not reported or not con-

toneal injection of 10 mg iron dextran three times per week during sidered in the majority of studies, it cannot be excluded that errors

four weeks in young Wistar rats [58]. In the 1-methyl-4-phenyl- during sample processing contribute to disparate results [91]. It

1,2,3,6-tetrahydropyridine (MPTP) PD mouse model it was shown should be also noted that routinely used metal analytical methods

that unilateral MPTP treatment can induce 100% increase in Fe con- such as AAS or ICP-MS alone cannot distinguish between different

centration in the ipsilateral SN after 3–6 months [59,60] along with metal species or oxidation states. Also, differences in total con-

decreased ceruloplasmin ferroxidase activity [61]. While exam- centration of a particular metal in a tissue may reflect differences

ining the timeline of consequences of MPTP treatment, it was in the content of metallo-proteins and enzymes (e.g. ceruloplas-

observed that Fe deposits in SN appeared 4.5 months after treat- min in the case of serum Cu [97] or glutamine synthetase in the

ment. Simultaneously a nigral cell loss of 40% had occurred [62] case of brain Mn [98]). Thus, finding of abnormal total tissue metal

indicating that Fe increase in the SN does not precede but may concentrations does not automatically implicate abnormal metal

follow the onset of neurodegenerative changes. Nigral cell dam- stores or abnormal labile (free) metal concentrations. Hyphen-

age in the 6-hydroxydopamine (6-OHDA) animal model of PD is ated techniques, notably high performance liquid chromatography

also accompanied by increased Fe levels in the SN [63]. (HPLC) and capillary zone electrophoresis (CZE) online with ICP-

Chelator pretreatment reduces degeneration of SN neurons in MS, have been used for studying Mn species in body compartments

MPTP, 6-OHDA and lactacystin-induced PD animal models [63–69]. of healthy subjects [99,100]. These studies documented that most

DMT1 upregulation has been documented in animal PD models. of the Mn-containing compounds found in liver were Mn-enzymes

Mice with dysfunctional DMT1 were partially protected against (for review see Ref. [101]). In order to better understand the role of

PD-inducing toxins, stressing the role of this protein in Fe medi- altered metal content in neurodegenerative diseases, similar spe-

ated degeneration [70]. Ceruloplasmin null mice develop increased ciation studies need to be performed in brain tissue and CSF of

nigral Fe levels accompanied by nigral cell loss, both of which were patients.

prevented by administration of the Fe binding agent deferiprone Using microscopic in situ imaging techniques with resolution at

[61]. the micro- or nanometer scale it was shown that Fe deposits in the

Intrastriatal injection of Mn has been shown to cause loss of SN of PD patients are predominantly associated with neuromelanin

dopaminergic cells [71]. Long-term exposure to Mn in developing in dopaminergic neurons [86,102] and there is evidence that Fe in

rats leads to impaired motor coordination and increased signs of these deposits is not strongly bound and thus potentially redox

oxidative stress in the striatum [72]. Contrary to results in humans, active. Suboptimal concentrations of the ferritin protein have been

Mn intoxication in rodents leads to a 20–75% reduction in the num- reported in the SN of PD patients and also in cases of incidental

ber of SN dopaminergic cells [73,74]. Lewy body disease [78,85,103–105]. Normal ferritin upregulation

Taken together, published data support the notion of Fe and Mn associated with increased Fe content during aging was absent in

toxicity directed toward nigral dopaminergic cells and protective PD patients due to sustained activity of iron regulatory protein 1

effects of Fe chelating agents such as deferiprone in animal models (IRP1) [106]. Ferritin is the main Fe storage compound in glial cells

of PD. and its decreased levels does not necessarily affect Fe metabolism in

neurons [107]. Interestingly, ferritin was shown to be a component

Dysregulation of brain metal homeostasis of neuromelanin granules suggesting its possible iron-regulatory

function also in neurons [108]. Moreover, neuromelanin granules

The majority of autopsy studies have reported 30–100% increase overloaded with Fe [10,81,83] exhibit higher level of redox activity

of Fe content in the SN of PD patients compared to age-matched in PD [109]. Taken together, these studies suggest that disrup-

controls but several studies did not confirm these findings. Possible tion of the ferritin complex along with other disturbances of Fe

reasons include different analytical methods [75] and pathophysi- regulation may eventually overwhelm the storage capacity of the

ological heterogeneity in PD [76]. One study indicated that the Fe neuromelanin system, which may lead to an increased labile Fe

content in the SN was not elevated in mildly affected but only in pool promoting the neurodegenerative process [110]. Increased

3+ 2+

advanced PD patients [77], suggesting that Fe increase may not Fe /Fe ratio in PD was also noted in two studies from the same

be involved in the early disease development. The majority of group, using spectrophotometric measurements on samples from

studies using inductively coupled plasma mass spectrometry (ICP- fresh frozen brains pretreated with hydrochloric acid and pepsin

MS) or atomic absorption spectroscopy (AAS) showed increased where ascorbic acid was used to reduce Fe. They concluded that an

3+ 2+

Fe concentration in PD [78–88] (Table 1). It has been argued that increased Fe /Fe ratio is a result of ongoing oxidative processes

negative results yielded by Mössbauer spectroscopy [89,90] are a [77,87]. This interpretation is speculative since conditions known

consequence of its relatively poor sensitivity compared to other to increase oxidative stress such as ischemic insult or Mn overload

2+ 3+

analytical techniques [91]. Coulometry performed using Ferrochem cause the opposite effect, that is an increased Fe /Fe ratio [111].

II, which was employed by Loeffler et al. [92], is known for inter- Moreover, this finding was disputed by other groups who did not

2+

ference with various substances [93] and it cannot be excluded find any detectable Fe iron in SN using Mössbauer spectroscopy

that interference with some compound in PD SN contributed to [89] and micro-XANES technique [112]. The abnormally high con-

2+

the negative results. centration of Fe might have been an artifact of the measurement

Measurement of metal concentrations in tissues is prone to technique used by Sofic et al. [91,113]. This is in line with the his-

3+ 2+

various biases such as instability of metal species during sam- tochemical distribution of Fe and Fe [114] and the finding that

ple preparation and analysis, sampling contamination, and metal the major Fe storage molecules in SN, ferritin and neuromelanin,

3+

leaching during tissue storage. In post-mortem studies tissue metal store Fe in the ferric (Fe ) form [115].

composition may differ from the living condition. Agonal changes Iron accumulation in PD is confined to the SN, while its lev-

including ischemia, BBB disruption and cessation of cell respira- els in the striatum and cerebral cortex are comparable to those of

tion might alter not only the redox state and labile metal pool controls or even decreased [116]. Results in the GP are inconclu-

proportion but also total tissue metal concentration as has been sive since both normal [77,87], increased [82,92] and decreased

documented for Fe during transient brain ischemia in rats [94]. [78,117] concentrations have all been reported. Also CSF studies

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Table 1

Concentration of metals in post-mortem basal ganglia and cortical tissue in PD patients.

Reference Method N Main findings (Fe, Cu, Mn content) Comments

↓

Ayton [61] AAS 10 ↑Fe in SN +42% Ferroxidase activity in SN

↓Cu in SN −51%

=Fe, Cu in frontal GM

Davies [145] SRXFMPIXE 5 ↓Cu in SN (neuromelanin) -50%, LC =Zn in SN, LC, occipital GM

(neuromelanin) −57% ↓Ctr1 in SN neurons

↑Fe in SN (neuromelanin) +37% ↑SOD1 in SN

=Fe, Cu in occipital GM

* ↑

Visanji [105] AAS 3 ↑Fe in SN +100% Ferroportin expression in SN

=Fe in Put, pons ↑Ferritin in Put

↓TfR in Put

↑

Szczerbowska- SRXFM 4 ↑Fe in SN (neurons) +60% Ca, Zn in SN (neurons)

Boruchowska (2012, =Cu in SN (neurons) ↑Rb, Zn in SN (non-neuronal tissue)

2004) [208], [209] =Fe, Cu in SN (non-neuronal tissue)

Barapatre (2010) [210] PIXE 6 =Fe in SN (neuromelanin/non-neuronal tissue) ↓Ca in SN (neuromelanin/non-neuronal tissue)

Wypijewska (2010) MS AAS 17 =Fe, Cu in SN ↑labile Fe in SN

[90] =Labile Cu in SN

3+

Only Fe detected in SN

↓

Popescu [117] XFM 1 ↑Fe in SN +40% Zn in SN, Gp, Put, CN, GM

↓Fe in GP, Put, CN, cGM

↓Cu in SN

Oakley [86] WDXMA 16 ↑Fe in SN (neurons) +100%

↑Fe in SN (neuropil) +70%

* ↑

Reinert (2007) [211] PIXE 1 =Fe in SN (neuromelanin) Ca in SN (neuromelanin)

*

↓Cu in SN (neuromelanin) −190% ↓Ni in SN (neuromelanin)

Morawski (2005) [212] PIXE 6 ↑Fe in SN (neuromelanin) +100%

=Fe (non-significant increase) in SN

(cytoplasm, glia)

↑

↑

Griffiths [82,88] AAS EXAFS 6 Fe in SN +100%, GP +43% Ferritin loading in SN

= Fe in Put, CN, cGM

3+

Galazka-Friedman [89] MS 6 =Fe in SN Only Fe detected in SN

* 3+

Kienzl (1995) [213] EDXMA 3 ↑Fe in SN (neuromelanin) Only Fe detected in SN

*

Jellinger [84] =Fe in SN (Lewy bodies, cytoplasm)

Loeffler [92] COL 14 =Fe in SN, Put, CN, frontal GM =Tf in SN, GP, Put, CN, frontal GM

*

↑Fe in GP

Mann [85] ICP-MS 18 ↑Fe in SN +56% =Zn in SN

=ferritin in SN

*

Good [81] LAMMA 3 ↑Fe in SN (neuromelanin) +45% ↑Al in SN (neuromelanin)

*

=Fe in SN (cytoplasm/neuropil)

↑

Dexter (1989) ICP-MS 27 ↑Fe in SN +35% Zn in SN, Put, CN

[214,78,79] ↓Fe in GP −29% =Pb in SN, cGM

↓Cu in SN −34%

=Mn in SN, Put, CN, cGM

=Cu in GP, Put, CN, cGM

=Fe in Put, CN, cGM

Hirsch [83] WDXMA 5 ↑Fe in SN (non-neuromelanin) +240% =Zn in SN

↑Fe in SN (Lewy bodies) +400% ↑Al in SN (Lewy bodies)

↓Fe in SN (neuromelanin) -35%

Riederer [77] AAS 13 ↑Fe in SN (only in severe degeneration) +35% ↑Zn in RN

↑Cu in RN =Ca, Mg, Zn in SN, GP, Put, CN, RN, cGM

=Fe in GP, Put, CN, RN, cGM ↑Ferritin in SN

3+ 2+

=Cu in SN, GP, Put, CN, cGM ↑Fe /Fe ratio

↓

Uitti [146] AAS, AES 9 ↓Cu in SN Mg in CN

=Fe in SN, CN = Ag, Al, As, B, Be, Ca, Cd, Co, Cr, K, Pb, Mn, Mo,

=Mn in SN, CN Na, Ni, P, Se, Ti, V, W, Zn in SN, CD

↑ 3+ 2+

Sofic [87] SPF 8 ↑Fe in SN +76% Fe /Fe ratio

=Fe in Put, GP, cGM

Earle [80] XFS 11 ↑Fe in SN, BG +100% =Zn in SN, BG

=Mn in SN, BG

AAS – atomic absorption spectroscopy, AES – atomic emission spectroscopy, ICP-AES – inductively coupled plasma-atomic emission spectrometry, ICP-MS – inductively

coupled plasma-mass spectrometry, SPF -spectrophotometry, MS – Mössbauer spectroscopy, (SR)XFM – (synchrotron radiation) X-ray fluorescence microscopy, PIXE –

particle induced X-ray emission, WDXMA – wavelength dispersive X-ray microanalysis, XFS – X-ray fluorescence spectroscopy, LAMMA – Laser Microprobe Mass Analysis,

EXAFS – Extended X-ray absorption fine structure, EDXMA – energy dispersive X-ray microanalysis, SN – substantia nigra, LC – locus coeruleus, Put – putamen, CN – caudate

nucleus, RN – red nucleus, BG – basal ganglia, (c)GM – (cortical) gray matter, Tf(R) – transferrin (receptor).

N = number of patients.

*

Not statistically significant or statistical analysis not performed.

have reported both normal [118–121] and decreased [122–124] Fe The cause of metal regulatory protein dysfunction in PD SN is

concentration in PD suggesting no overall Fe increase in the CNS unknown. Several genes involved in the causation of PD are related

(Table 2). Here it is important to note that speciation analysis was to the metabolism of metals [126] and mutations in DMT1, cerulo-

not performed in these CSF studies and neither abnormal cellular Fe plasmin and transferrin were found to be weakly associated with

2+ 3+

handling, Fe /Fe dysbalance nor increased proportion of labile the risk of developing PD [127–129]. Several studies have docu-

Fe can be excluded. Alteration in Fe balance can be suspected since mented abnormalities in ceruloplasmin function in PD. Specifically,

decreased CSF ferroxidase activity (see below) has been found in decreased ferroxidase activity was found in plasma [130,131],

PD [125]. CSF [125,132] and post-mortem SN tissue [61]. Dysfunction of

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Table 2

Concentration of metals in the CSF of PD patients.

Reference Method N Main findings Comments

Hozumi [119] ICP-MS 20 ↑Cu +80%, Mn +70% ↑Zn +174%

=Fe =Mg

Boll [132] AAS 22 ↑Cu +230% (free) Free Cu correlated with motor impairment

↓

Alimonti [122] ICP-AESSF-ICP-MS 42 ↓Fe −20% Co, Cr, Pb, Si, Sn

=Cu, Mn =Al, Ba, Be, Bi, Ca, Cd, Hg, Li, Mg, Mo, Ni, Sr, Tl, V, W, Zn, Zr

Bocca [123] ICP-AESSF-ICP-MS 91 ↓Fe −37%, =Cu, Mn ↓Si

* ↓

Forte [124] ICP-AESSF-ICP-MS 26 ↓Fe −55% Si

=Cu, Mn =Al, Ca, Mg, Zn

Boll [125] AAS 49 =Cu (total) Ferroxidase activity/total Cu inversely related to PD stage

Jimenez-Jimenez [121] AAS 37 =Fe, Mn, Cu ↓Zn

Gazzaniga [118] AAS 11 =Fe, Mn, Cu

Pall [120] AAS 31 =Fe, Mn ↑Cu (free) confirmed by

↑Cu phenantroline-copper assay

AAS – atomic absorption spectroscopy, AES – atomic emission spectroscopy, ICP-AES – inductively coupled plasma-atomic emission spectrometry, ICP-MS – inductively

coupled plasma-mass spectrometry.

N = number of patients.

*

Not statistically significant or statistical analysis not performed.

ceruloplasmin may be a consequence of oxidative changes in dysfunction of the blood–CSF barrier similar to the situation in

this enzyme [133]. Decreased ferroxidase activity was found WD [147].

to be associated with earlier disease onset [134,135] and with Abnormal concentrations of Mn have not been reported in

markers of iron deposition in the SN of PD patients [129,136,137]. PD brains [78–80,146], but all published studies are rather old.

Other studies have reported abnormal expression of Fe regulatory The majority of studies also found normal Mn levels in the CSF

proteins. Nigral cells behave as if they were Fe deficient in PD; [118,120–124].

expression of proteins involved in iron uptake as DMT1, TfR2

and lactotransferrin receptor (LTFR) is upregulated [138,139],

Wilson’s disease (WD)

whereas expression of proteins involved in iron efflux such as

FPN1 is downregulated [140]. SN areas with the most severe

WD is a genetic disorder caused by mutation of the ATP7B

cell degeneration showed an increased LTFR expression [139]. At

protein which is mostly expressed in the liver [148]. Dysfunc-

the cellular level, regulation of Fe metabolism is dependent on

tion of ATP7B leads to disturbed Cu metabolism with a gradual

mitochondria where Fe is incorporated into iron-sulfur (Fe S)

accumulation of Cu in the body and reduced synthesis of various

clusters by the action of a complex of multiple enzymes. Fe S

cuproproteins, in particular ceruloplasmin. The traditional view on

clusters are prosthetic groups necessary for proper function of

the pathophysiology of neurologic symptoms in WD holds that

several proteins such as Complexes I–III of oxidative phosphory-

overwhelming of the liver storage capacity for Cu leads to its

lation, ubiquinone and aconitase. The latter is also known as iron

spillage into plasma and CSF, leading to cellular uptake and oxida-

responsive element binding protein 1 (IREB1) since it is involved

tive damage in the CNS [149], although alternative theories have

in the regulation of the transcription of Fe transport proteins.

been proposed [150]. However, ATP7B is expressed also in the brain,

Low level of Fe S cluster production leads to low cytoplasmic

namely in the choroid plexus, basal ganglia, cerebellum and cor-

aconitase activity and increased transcription of TfR and DMT1

tex [145] and its dysfunction may lead to neurological symptoms

[141]. Upregulation of Fe uptake may be related to mitochondrial

through other mechanisms than just overflow of hepatic Cu. ATP7B

dysfunction associated with decreased Fe S cluster synthesis,

dysfunction in astrocytes may hypothetically lead to impaired

which was documented in nigral cells in PD [142]. Alternatively, it

production of ceruloplasmin with the possible consequence of

has been show that iron regulatory protein 2 (IRP2) is degraded by

impaired Fe efflux, similar to the situation in aceruloplasminemia

the ubiquitin–proteasome system and its dysfunction may lead to

[151]. It has been shown that ATP7B is expressed in the choroid

high IRP2 levels which in turn stimulate production of DMT1 [143].

plexus and its dysfunction may hamper the elimination of excess

Concerning Cu, greater variation in Cu metabolic profiles has

65 Cu across the blood–CSF barrier [152].

been shown in PD compared to healthy controls using Cu

The combined evidence of animal, neuroimaging, CSF and post-

isotope tracer. Most importantly, higher peak plasma Cu val-

mortem metal studies (see below) suggests that metals other than

ues were documented suggesting more efficient absorption in

Cu may accumulate in WD.

the gut [144]. Increased concentration of redox available Cu has

been reported in PD CSF [120] and its concentration was corre-

lated with motor impairment [132]. The SN contains high levels Local dysregulation of metal homeostasis

of Cu in healthy subjects [145]. The decrease in total Cu con-

centrations reported in the SN in the majority of studies in In patients with the neuropsychiatric form of WD, measure-

PD patients [61,78,102,146] may be a reflection of loss of the ments of Cu in CSF and post-mortem brain tissue clearly show that

cuproproteins superoxide dismutase 1 (SOD1) or ceruloplasmin. Cu concentrations are diffusely increased in the CNS up to 850% of

In post-mortem PD SN tissue normal SOD1 activity was found normal levels [153] (Table 3). With chelating treatment it takes

[102]. Moreover, decreased Cu levels are not accompanied by sim- up to 4 years for CSF Cu concentrations to normalize [154,155]

ilar decreases in zinc (Zn) levels in the majority of post-mortem and high levels are a marker of non-compliance [156]. Profound

studies (Table 1) which would be expected in the case of SOD1 Cu accumulation is still persistent in all brain regions after 10

loss. Currently, it seems more likely that decreased SN Cu lev- months of chelating treatment as shown by post-mortem studies

els is a consequence of reduced ceruloplasmin content which [157–159]. Another post-portem study showed abnormal brain Cu

is in line with the low ceruloplasmin ferroxidase activity found deposits even after several years of chelating treatment, and also

in SN [61]. Increased labile Cu in the CSF of PD patients may that the severity of neuropathological findings was correlated with

be caused by its impaired incorporation into cuproproteins or cerebral copper content [160].

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6 P. Dusek et al. / Journal of Trace Elements in Medicine and Biology xxx (2014) xxx–xxx

Table 3

Concentration of metals in the CFS and brain tissue in WD.

Reference Method N Type of tissue Main findings Comments

Kodama [153] AAS 4 (2 neu, 2 hep) CSF ↑Cu in neuro WD +280% =Zn

=Cu in hepato WD ↓Cp concentration

Cu decreases with therapy

Stuerenburg [155] AAS 4 (neu) CSF ↑Cu WN Cu decreases with therapy

Weisner [154] AAS 5 (neu) CSF ↑Cu +330% ↓Cp concentration

Cu decreases with therapy

*

Cumings (1948) [158] COL 3 Brain ↑Cu in CN(+160%), Put(+600%), thal(+380%), GP(+60%),

WM(290%), GM(+320%)

*

↑Fe in CN(+100%), Put(+20%), thal(+160%), WM(+38%),

GM(+140%)

=Fe in GP

** ↓

Faa [159] ICP-AES 1 Brain ↑Cu in all brain regions Mg, Zn, Ca in all brain

**

↓Fe in all brain regions regions

↑

Litwin [157] ICP-MS 12 (10 neu, 2 hep) Brain Cu in Put(+540%), DN(+590%), pons(+540%), frontal =Zn in Put, DN, pons, frontal

GM(+850%) GM

↑Fe in ND(+74%)

=Fe in Put, pons, frontal GM

=Mn in Put, DN, pons, frontal GM

AAS – atomic absorption spectroscopy, COL – colorimetry, ICP-AES – inductively coupled plasma-atomic emission spectrometry, ICP-MS – inductively coupled plasma-mass

spectrometry.

SN – substantia nigra, DN – dentate nucleus, Put – putamen, CN – caudate nucleus, GM – gray matter, WM – white matter.

Neu – neuropsychiatric form, hep – hepatic form, N = number of patients.

*

No statistical analysis performed.

**

No control group, compared to published reference values.

Increased Fe content has been reported in the striatum, gray because it decreases the availability of Cu for ceruloplasmin

matter, white matter [158] and dentate nucleus of the cerebellum production. Zinc treatment can have opposite effects [174]. No

[157] in post-mortem studies. The latter study reported normal difference in brain Fe concentration was however found between

brain Mn concentrations, but Mn was not measured in the GP which patients treated with Zn and penicillamine [157]. Ceruloplasmin

is the structure with the greatest predisposition toward accumu- also interacts with Mn and its decreased activity can alter the neu-

lation of Mn and other divalent metals [26]. In fact, MRI studies rotoxicity of Mn [175].

indicate that elements such as Fe and Mn may also accumulate in Altogether, these data suggest that profoundly increased Cu con-

the brain over the course of WD. T1 hyperintensities in GP are sug- centrations in the CNS of WD patients persist for a long time during

gestive of Mn deposits in patients with the hepatic form of WD chelating treatment and that local accumulation of Fe in certain

[161,162]. Several MRI studies documented T2 hypointensities in brain nuclei may occur during the course of WD.

GP and other brains regions in WD patients suggestive of deposits

with paramagnetic properties [163–167]. It has been suggested that Animal models

2+

the GP changes might reflect Cu deposits [168], since Cu species

are paramagnetic. However, little is known of which form Cu is Established animal models for WD are the Long Evans Cinnamon

deposited in the WD CNS, and another possibility is that these T2 (LEC) rat [176], the toxic milk mouse [177] and the Atp7b(−/−)

hypointensities correspond to the paramagnetic effect of ferritin- mouse [178]. In LEC rats markedly increased concentrations of

iron. It has been documented that the area of T2 hypointensities loosely bound Cu were found in liver and plasma when total Cu con-

increases during chelating treatment but it seems unlikely that centration exceeded the capacity of liver metallothionein synthesis

this is due to increased brain Cu concentrations [165]. Indeed, a [179–181]. Increased brain Fe levels have been demonstrated in

PET study with radioactively labeled Fe in human subjects showed LEC rats [182] and low Fe diet as well as Fe removal by phlebotomy

increased brain Fe uptake in WD patients compared to healthy was beneficial in terms of decreased oxidative stress markers in

volunteers [169]. the liver [183,184]. Treatment with Zn not only reduced the liver

Iron accumulation in WD may be a consequence of low cerulo- damage through induction of metallothionein expression but also

plasmin levels. However, it has been reported that as little as 10% of led to decreased liver Cu and Fe concentrations in LEC rats [185].

the normal plasma level of ceruloplasmin was sufficient for normal In the toxic milk mouse, increased Cu stores were found in all tis-

Fe metabolism in a pig model [170] and in liver preparations [171]. sues, but elevated Fe was present only in the kidneys, possibly as a

This finding was confirmed in WD patients in whom defective Fe result of hemolysis [186]. The brain Fe content was even decreased

metabolism was observed only in those who had ceruloplasmin in the hippocampus [187]. Penicillamine treatment in these mice

levels less than 5% of the normal range [172]. The fact that most increased labile Cu in plasma and brain tissue as a result of its

WD patients have more than 10% of the normal level of cerulo- mobilization from the large tissue deposits and enhanced oxida-

plasmin also argues against gross changes in Fe metabolism in this tive stress, which may explain the initial worsening seen in human

disease. Although some authors reported elevated liver Fe concen- patients [188].

tration in WD patients [151], results of the largest published study In the Atp7b(−/−) mouse imaging of Cu metabolism using

64

argue against a clinically relevant elevation of Fe in the liver in the ingested Cu showed Cu accumulation in liver but not in brain

majority of patients [173]. This, however, pertains to peripheral Fe [189]. In the same WD model decreased ferroxidase activity of

metabolism and CNS may be more susceptible to oxidative damage ceruloplasmin was related to decreased levels of serum Fe and

caused by decreased ceruloplasmin function. Another factor con- transferrin saturation [190]. In contrast, Cu intoxication itself does

tributing to the risk of Fe accumulation may be mode of treatment. not cause Fe accumulation in liver or brain of rats [191]. This find-

Standard penicillamine chelation does not remove Fe from the ing suggests indirectly that decreased ceruloplasmin, rather than

organism; conversely it may lead to higher tissue Fe accumulation Cu toxicity, affects impaired Fe homeostasis in WD.

G Model

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P. Dusek et al. / Journal of Trace Elements in Medicine and Biology xxx (2014) xxx–xxx 7

Concluding remarks larger groups of WD patients and studies validating the use of brain

MRI in determining the regional distribution of specific metals.

Current data from studies measuring metal concentrations in

brain tissue and CSF do not support the idea of a general metal Conflict of interest

accumulation in the entire CNS of PD patients. Local dysregulation

The authors have no conflict of interest.

of Fe metabolism seems to occur in the SN, at least in a sub-

group of PD patients. The pathophysiological relation of iron to

Acknowledgments

neurodegeneration and why it selectively affects the SN remains

unanswered. It has been suggested that dopamine producing cells

This work was supported by the Czech Ministry of Education,

are particularly vulnerable to metallotoxic effects [192]. One of the

research project PRVOUKP26/LF1/4 and by the Czech-Norwegian

vulnerable enzymes in the dopamine synthesis pathway may be

Research Programme CZ09.

tyrosine hydroxylase, which requires appropriate amounts of iron

and molecular oxygen as cofactors. Animal data as well as follow-

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