Copper is a biometal essential for normal brain development and function, thus copper deficiency or excess results in central nervous system disease. Well-characterized disorders of disrupted copper homoeostasis with neuronal degeneration include Menkes disease and Wilson's disease but a large body of evidence also implicates disrupted copper pathways in other neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease and prion diseases. In this short review we critically evaluate the data regarding changes in systemic and brain copper levels in Parkinson's disease, where alterations in brain copper are associated with regional neuronal cell death and disease pathology. We review copper regulating mechanisms in the human brain and the effects of dysfunction within these systems. We then examine the evidence for a role for copper in pathogenic processes in Parkinson's disease and consider reports of diverse copper-modulating strategies in in vitro and in vivo models of this disorder. Copper-modulating therapies are currently advancing through clinical trials for Alzheimer's and Huntington's disease and may also hold promise as disease modifying agents in Parkinson's disease.

INTRODUCTION

A complex and self-perpetuating cascade of events, including oxidative stress, protein aggregation, mitochondrial dysfunction and inflammation are responsible for neuronal death in Parkinson's disease [1]. Changes in brain metals play a key role in several of these cell death pathways. For example, increased iron levels in the vulnerable substantia nigra in Parkinson's disease have been implicated in increased free radical production and protein aggregation [2], stimulating a search for potentially neuroprotective iron modulating therapies for this disorder. Iron changes, and potentially therapeutic iron modulation, in Parkinson's disease have been extensively reviewed, but to date clinical trials of brain iron modulation in this disorder have proved disappointing [3,4]. Given the key roles of a number of biometals in the brain, and the inherent redundancy associated with some metal transport pathways, metals research in Parkinson's disease now includes such metals as copper, zinc, magnesium, selenium and manganese. A growing body of evidence links disruptions in brain copper homoeostasis and copper-associated pathways to cell death in Parkinson's disease, suggesting that modulation of brain copper may represent an additional target for the development of novel protective therapies for this disorder.

The role of copper in neurological disorders such as Menkes and Wilson's disease is well-established, and has been extensively reviewed [5,6]. In contrast, the role of copper in Parkinson's disease has not received the same attention. In this article we review the distribution and transport of copper in the healthy brain. We then critically discuss reports of changes to systemic and brain copper levels in Parkinson's disease. We review research suggesting a role for copper in α-synuclein toxicity, as well as in other well-recognized cell death pathways in Parkinson's disease including mitochondrial dysfunction and oxidative stress. We conclude with an update on novel therapeutic strategies which aim to restore copper homoeostasis and their potential for treatment of Parkinson's disease.

COPPER IN THE HEALTHY BRAIN

Although copper is distributed throughout the brain, markedly higher levels are found in the substantia nigra, cerebellum and hippocampus [7,8]. This differential distribution has been suggested to reflect an increased requirement for, or storage, of copper in these regions [7,8]. For example, data from our laboratories suggest that the presence of the unique metal-binding pigment neuromelanin in the human substantia nigra may account for the high concentration of copper, and other transition metals such as iron, in this region of the human brain [9]. Copper is an essential trace element incorporated as a catalytic and structural cofactor in multiple enzymes crucial for neurological development and function [10]. In excess, however, copper is toxic as it can participate in reactions that generate free radicals, thus contributing to oxidative stress [11]. Mechanisms that regulate copper uptake, distribution and utilization, storage, detoxification and efflux in the brain can therefore critically influence neuronal health and function.

The copper transport protein Ctr1 in the choroid plexus [12,13], as well as the copper transporting ATPases, ATP7A and ATP7B regulate copper homoeostasis in the brain. ATP7A and ATP7B are differentially localized to the basolateral and apical membranes of the choroid plexus and mediate copper transfer into capillaries and the cerebrospinal fluid (CSF) respectively [7]. Once copper enters the CSF and forms small complexes with albumin or amino acids, its cellular transport within the brain appears to be similar to that reported in mammalian peripheral tissues (Figure 1) [14]. Copper is transported into the cytoplasm of neurons by Ctr1 [13]. This occurs following reduction of copper (II) (Cu2+) to copper (I) (Cu1+), thought to be facilitated by the Steap family of metalloreductases [15]. Cytoplasmic copper rapidly associates with other molecules such as metallothionein proteins and glutathione, which bind copper for storage and/or detoxification [16], and metallochaperone proteins, which deliver copper to biosynthesis and metal-transfer sites within the cell. One such chaperone protein, Atox1, binds to Cu1+ and transfers it to ATP7A and ATP7B in the trans-Golgi network [10]. ATP7A and ATP7B mediate the incorporation of copper into newly synthesized cuproproteins, such as the glial-based ferroxidase enzyme ceruloplasmin, which is also the major copper carrying protein in the blood, and in addition plays a role in iron metabolism [17]. ATP7A is also suggested to play a role in efflux of excess copper from the cell (Figure 1) [10]. The critical role of copper transport proteins such as ATP7A and ATP7B is demonstrated by Menkes and Wilson's diseases where genetic mutations in these proteins result in severely disrupted copper homoeostasis and resultant neurological disease. Further, the importance of cuproproteins such as ceruloplasmin in brain health is demonstrated by aceruloplasminaemia, a severe and progressive neurodegenerative disease associated with brain iron accumulation resulting from a mutation in the gene for this protein [18,19]. In yeast, copper chaperone for superoxide dismutase (CCS) is essential for the activation of the antioxidant protein copper/zinc superoxide dismutase 1 (SOD1) [20] and another chaperone protein, cytochrome c oxidase copper chaperone protein (Cox17), is thought to transport Cu1+ to mitochondria [21], although other yet unidentified carriers may also be involved [2224]. Nonetheless, in the mitochondria Cox17, and associated proteins including Sco1, Sco2 (synthesis of cytochrome c oxidase subunit 1 and 2 respectively), and Cox11 (cytochrome c oxidase assembly homologue 11), play essential roles in the metallation of cytochrome c oxidase (COX) by Cu1+ [25,26], and thus the activation of COX complex IV in the respiratory electron transport chain [27,28].

Model of cellular copper homoeostasis

Figure 1
Model of cellular copper homoeostasis

Model of mammalian cellular copper transport where copper ions are transported into the cell by Ctr1 and distributed to different cellular locations by copper transport proteins. The copper transport protein Atox1 is suggested to transport copper to the ATPases, ATP7A and ATP7B, in the late Golgi. Cox17, Sco1 and Sco2 are involved in the trafficking of copper to the mitochondria for incorporation into COX. CCS delivers copper to copper/zinc superoxide dismutase (Cu/Zn SOD/SOD1). The ATPases are involved in the excretion of copper from the cell and in the incorporation of copper into newly synthesized cuproproteins. Within the cell, metallothionein chelates most available copper and is critical for cell survival in an environment of copper excess.

Figure 1
Model of cellular copper homoeostasis

Model of mammalian cellular copper transport where copper ions are transported into the cell by Ctr1 and distributed to different cellular locations by copper transport proteins. The copper transport protein Atox1 is suggested to transport copper to the ATPases, ATP7A and ATP7B, in the late Golgi. Cox17, Sco1 and Sco2 are involved in the trafficking of copper to the mitochondria for incorporation into COX. CCS delivers copper to copper/zinc superoxide dismutase (Cu/Zn SOD/SOD1). The ATPases are involved in the excretion of copper from the cell and in the incorporation of copper into newly synthesized cuproproteins. Within the cell, metallothionein chelates most available copper and is critical for cell survival in an environment of copper excess.

In addition to CCS [29], the regional and cellular distribution of the copper transport proteins Ctr1, ATP7A, ATP7B and Atox1 has been characterized in the human brain, where their expression is positively associated with regional copper levels [7]. Copper transport proteins are tightly regulated in the mammalian brain, suggesting that these proteins are a primary mechanism to control cellular copper levels, to respond to temporal changes in cuproenzyme requirements for copper [25,30,31] and to guard against potentially damaging cellular copper excess [32].

Disrupted copper homoeostasis in the brain results in striking neurological pathologies which, if left untreated, may lead to neuronal degeneration and death, such as that observed in Menkes [33] and Wilson's diseases [34]. The cause and consequences of disrupted copper homoeostasis in these diseases is well established. In contrast the role of copper in Parkinson's disease is not yet well understood but recent data demonstrate early changes in the regional distribution of copper in the brain in Parkinson's disease. Further there is increasing evidence for a role for copper in neurodegenerative mechanisms characterizing this disorder.

SYSTEMIC AND BRAIN COPPER LEVELS IN PARKINSON'S DISEASE

Total copper levels within the blood, CSF and the brain are the sum of different pools of copper; free copper and copper bound to proteins. In the blood approximately 80–95% of copper is bound to ceruloplasmin, and non-ceruloplasmin copper is loosely bound and exchanged among albumin, transcuprein, alpha 2 macroglobulin and low molecular weight compounds. In the CSF only ∼35% of total copper exists in association with ceruloplasmin [35]. Ceruloplasmin-bound and non-ceruloplasmin-bound copper levels in the blood have proven useful in the diagnosis of multiple copper-related neurological diseases, and have helped better understand disease pathology. Defective ATP7B function in Wilson's disease, for example, results in impaired incorporation of copper into ceruloplasmin in the liver and impaired excretion of copper into bile, resulting in hepatic copper accumulation. Plasma copper is low, as the bulk of it is normally bound to ceruloplasmin, and plasma ceruloplasmin levels are low because ceruloplasmin is degraded more rapidly when not bound to copper [36]. Copper accumulated in the liver causes oxidative damage to hepatocytes [37,38], leading to necrosis and the release of non-ceruloplasmin copper into the plasma. This copper enters the CSF and brain tissues and accumulates equally throughout the brain [39], leading to neurological and neuropsychiatric disease. However, studies in mouse models suggest that this mechanism is only one part of the story and that the copper distribution between tissues can be modified by alterations in the regulation of copper transport proteins. For example, it has previously been demonstrated that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine of a mouse model of Wilson's disease [40]. Instead, the urinary copper increase is associated with the hepatic down-regulation of Ctr1, which allows switching to a small copper carrier (SCC)-mediated removal of copper via kidney when liver function is impaired [40]. Further, although the ATP7A gene appears silent in normal liver, copper deficiency in the mouse heart signalled an adaptive stress response to mobilize copper from the liver, unveiling a new pool of liver copper that is capable of being mobilized [41].

Copper pathways in Parkinson's disease are less well characterized and do not currently represent a valid diagnostic marker or prediction tool in Parkinson's disease. Most studies of Parkinson's disease patients have reported total serum or plasma copper levels, rather than individual levels of the different pools of copper. Theoretically, as the concentration of non-ceruloplasmin-bound copper is very low relative to total serum copper concentrations, a clinically significant change in the highly reactive pool of non-ceruloplasmin-bound copper may not be apparent if total copper concentrations alone are measured. Furthermore, data from the few studies of copper levels in blood in Parkinson's disease are highly heterogeneous. However atomic absorption spectrophotometry shows that blood levels of copper and ceruloplasmin, in serum or plasma, are unaltered in Parkinson's disease, regardless of whether total or non-ceruloplasmin-bound copper is measured [4248]. Further, a meta-analysis of nine studies on copper levels in serum and four studies in plasma found no consistent difference between levels in Parkinson's disease patients compared with controls [48], and, although heterogeneity in the data are noted, the different analysis methods used had a negligible effect [48]. Taken together, these findings suggest that copper and ceruloplasmin levels in the blood are unaltered in Parkinson's disease and therefore are unlikely to represent a valid diagnostic marker or prediction tool in Parkinson's disease.

Another tissue available for peripheral sampling is CSF and data from other disorders suggest that CSF copper levels may reflect levels in the brain. In untreated Wilson's disease, for example, CSF copper concentrations are elevated, and fall with treatment and CSF copper levels have been suggested as a useful tissue to monitor the efficacy of chelation treatment in this disorder [39]. An early study of CSF copper levels in 24 Parkinson's disease patients and 34 age-matched controls reporting increased copper [45] has since been challenged by a larger number of studies, including a previous meta-analysis including a pooled total of 215 Parkinson's disease subjects and 119 controls, which find no changes in CSF copper or ceruloplasmin levels in Parkinson's patients compared with healthy age-matched controls [43,44,4851]. Overall the data suggest that any potential perturbations in copper levels in the Parkinson's disease brain are not mirrored in CSF perhaps because, unlike Wilson's disorder, the perturbations in copper levels, like the characteristic cell death in Parkinson's disease, are highly localized within the brain [52].

In the brain the majority of copper is not free but is tightly regulated by being bound to a range of molecules, including copper transport proteins recently described in the human brain [7]. Total copper levels in fresh-frozen [5255] and fixed [56,57] substantia nigra in Parkinson's disease have been consistently reported to be decreased by 34–51% compared with age-matched healthy controls [5254,5658]. Copper levels are also reduced in the caudate, the terminal field of these neurons, whereas copper in other brain regions remains unaffected [54]. A reduction in whole tissue copper levels in the substantia nigra in Parkinson's disease could theoretically be attributed to the marked neuronal cell loss occurring in this brain region. Consistent with preliminary reports [56,59], however, we have used two sensitive biochemical imaging methods, synchrotron radiation X-ray fluorescence microscopy and particle induced X-ray emission microscopy, to confirm marked decreases of 55–65% in intraneuronal copper at the single cell level which is restricted to the vulnerable substantia nigra and locus coeruleus in the Parkinson's disease brain [52]. This regional deficit in copper in Parkinson's disease is even more remarkable when one considers the normally high levels of copper in these regions in the healthy brain [7]. Further, we showed that intraneuronal copper levels are also similarly reduced in the substantia nigra in cases of Incidental Lewy body disease, thought to represent preclinical Parkinson's disease [52], suggesting that these changes occur early in the disease process and are independent of treatment [52]. Taken together, these reports link a significant decrease in copper at both the tissue and single cell level, to the vulnerability of specific brain regions to degeneration in Parkinson's disease. These findings suggest a role for copper in the pathogenesis of Parkinson's disease and have generated interest in the role of copper in the cell death pathways characteristic of Parkinson's disease.

COPPER AND α-SYNUCLEIN

Pathologically, Parkinson's disease is characterized by the formation of primarily intracellular α-synuclein-containing inclusion bodies called Lewy bodies. The current understanding of neuronal death in Parkinson's disease supports a role for α-synuclein in brain cell death via the formation and assembly of these protein aggregates. Experimental evidence demonstrates a direct interaction of copper and α-synuclein; Cu2+ binds to α-synuclein at two distinct domains and the co-ordination chemistry has been reviewed [6,60]. Cu1+ can also bind directly to α-synuclein at two distinct regions [61]. Within the cell, both copper species coexist and, theoretically, the transition from Cu2+ to Cu1+ could enhance intracellular levels of reactive oxygen species promoting cell damage [61]. For example, the intracellular reduction of α-synuclein-bound Cu2+ to Cu1+ may increase production of highly reactive H2O2 [61]. Further, the propensity of α-synuclein to aggregate following the binding of copper is increased, possibly resulting from the copper-catalysed site-specific oxidation of the protein which has been demonstrated under physiological conditions [61]. High copper levels promote the formation of oligomeric (toxic) forms of α-synuclein [6265] and quantum and molecular mechanics simulations demonstrate that copper attachment to α-synuclein results in the development of a secondary structure which favours its misfolding [65]. We have shown that the earliest deposition of α-synuclein in the parkinsonian substantia nigra occurs on neuromelanin [66], and copper levels, including those associated with neuromelanin, are significantly higher in the healthy substantia nigra and locus coeruleus compared with other brain regions [7,9]. Although with time α-synuclein pathology becomes widespread in the Parkinson's disease brain, the high level of copper in these vulnerable pigmented regions may increase the propensity for α-synuclein to accumulate in these regions in early stages of disease.

Another vulnerability factor in the parkinsonian substantia nigra is dopamine. In vitro studies demonstrate that copper and dopamine cooperatively bind to α-synuclein at different sites and enhance both the propensity for α-synuclein to oligomerize [67] and the production of reactive oxygen species [68]. In combination with dopamine, Cu2+ induces a different mechanism of α-synuclein oligomerization, cross-linking with a non-covalent bonding, compared with the likely radical-mediated covalent modification associated with dopamine alone [68]. The oligomerization of α-synuclein in the presence of copper can also be enhanced by the dopamine metabolites [66]. In vitro data suggest cellular copper levels may also influence toxicity of α-synuclein as copper supplementation of cell cultures overexpressing α-synuclein increased cytotoxicity [67]. In vitro data further suggest a link between copper, cellular localization of α-synuclein and propensity for aggregation. In a human neuroblastoma cell line, copper depletion results in the redistribution of α-synuclein towards the plasma membrane and reduces aggregate formation, although copper supplementation restores its cytosolic localization and its propensity for aggregation [69]. In contrast, a more recent report suggests that copper does not alter membrane-bound α-synuclein conformation or enhance the release of the protein from the membrane surface, despite addition of up to 10-fold excess of Cu2+ [68]. Such in vitro studies demonstrate the interest in the interactions between copper and α-synuclein but should be interpreted with caution as the relationship between copper levels used and the regional concentrations of copper found in the human brain [7,8] are unclear. Further, the majority of in vitro studies on Cu2+–α-synuclein complexes predate an interest in the acetylated form of the protein, most commonly found in the brain [70], and the commonly accepted picture of the Cu2+–α-synuclein complex is rooted in a nonacetylated α-synuclein model [71]. Recent findings however, suggest that the acetylated form of α-synuclein, has a lower affinity for Cu2+ and fails to demonstrate enhanced fibrillation at equimolar Cu2+ concentrations compared with the nonacetylated model [61,71]. Further, acetylation induces a modest population of α-helical conformation for the first six residues and enhances the lipid binding properties of the protein [72]. The importance of the cellular compartmentalization of copper and α-synuclein is also unclear and requires further investigation. For example, it is hypothesized that if copper levels in the cell change, copper may re-distribute between the different cellular compartments thus modulating the likelihood of α-synuclein aggregation [73].

COPPER-CONTAINING PROTEINS AND OXIDATIVE STRESS IN THE PARKINSON'S DISEASE BRAIN

Considerable evidence from modelling studies suggests that copper deficiency is associated with motor dysfunction, impaired mitochondrial function and antioxidant capacity, all of which have been reported in the substantia nigra in Parkinson's disease. For example, copper deficiency in the rodent brain is associated with neurological disturbances including tremors, ataxia and hypokinesia, as well as reduced striatal dopamine levels, neuronal degeneration, and altered mitochondrial morphology [7476]. Further, neuronal SOD1 and COX activities are impaired [7779] in animal and cell culture models of copper deficiency and ATP content is reduced [78,79]; changes consistent with apoptosis [78] and an increased susceptibility to proapoptotic molecules acting through oxidative stress [79]. These data demonstrate some of the molecular pathways affected by a central copper deficiency and suggest that midbrain dopaminergic function is negatively affected by changes within these pathways. In support of this hypothesis, a profound decrease in the specific activity of the copper-containing ferroxidase ceruloplasmin is reported in the substantia nigra of Parkinson's disease patients compared with age-matched controls [58]. Ceruloplasmin plays a key role in cellular iron transport and this change has important implications for the iron accumulation and subsequent oxidative stress occurring in this brain region in Parkinson's disease [52]. Another important cuproprotein in the brain is SOD1. In vivo, SOD1 scavenges superoxide radicals, acting as the first line of defense against reactive oxygen species [80], and has been suggested to represent a novel therapeutic target for treatment of Parkinson's disease [81]. An increase in SOD1 specific activity is the normal functional response in a highly oxidative cellular environment and increases cellular survival following various types of oxidative challenge, including that associated with the common Parkinson's disease model toxin 6-hydroxydopamine [82]. In Parkinson's disease, decreased activity of SOD1 is reported in erythrocytes [83] and CSF [84] and, consistent with the expected functional response of SOD1 in a highly oxidative cellular environment, we have demonstrated enhanced SOD1 specific activity (activity normalized to protein levels) in brain regions accumulating abnormal α-synuclein but without cell loss in the Parkinson's disease brain [52]. This increase, however, is not observed in the copper-deficient substantia nigra [52]. These data suggest that decreased copper bioavailability in the Parkinson's disease substantia nigra compromises the function of local cuproproteins with functional implications for identified cell death pathways in this brain region. Further support for this hypothesis can be drawn from animal modelling studies where copper pre-treatment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice preserves striatal dopamine content and attenuates dopamine neuron loss in a dose- and time-dependent manner [85,86]. The neuroprotective effects of copper in this model are suggested to be mediated by activation of copper-dependent proteins such as SOD1 [87], or by dampening the activities of proteins implicated in dopamine synthesis failure [86]. Conversely, animals lesioned with MPTP following copper chelation treatment suffer potentiated oxidative stress and neuronal loss [88].

The preferred route for SOD1 copper loading and activation is most likely to occur via CCS [20], whose mechanism of copper insertion and SOD1 activation has been elucidated [20,8991]. CCS is, however, no longer believed to represent the sole means to activate SOD1 in vivo. Recently Girotto et al. [81] have posited a putative role for DJ-1 as a copper chaperone. This protein is associated with both inherited and sporadic Parkinson's disease and has been suggested to cooperate with SOD1 in the same oxidative stress response pathway in that copper, most likely in the Cu1+ form, is transferred from the copper-DJ-1 complex to SOD1. This is supported by studies demonstrating copper transfer between the two proteins where activation through CCS was impaired [81]. Further, DJ-1 null mice are more susceptible to MPTP following a failure to up-regulate SOD1 expression [92], suggesting that DJ-1 may not only act as a copper chaperone able to rescue SOD1 activity, but also enhances expression of SOD1. Research on DJ-1 in the human brain is limited, but unusually high levels of DJ-1 are reported in the brain in Parkinson's disease, compared with the distribution of DJ-1 isoforms in normal brain tissue [93], suggesting conditions of enhanced oxidative stress alter expression of this protein. Further research into DJ-1 in the human brain is warranted to further our understanding of its potential role in copper regulation and oxidative stress response.

NOVEL THERAPEUTIC STRATEGIES FOR PARKINSON'S DISEASE

Marked changes in functionally important cuproproteins suggest that correction of intracellular copper bioavailability may benefit individuals with Parkinson's disease. Sophisticated pharmaceutical approaches are now being implemented to correct brain copper levels and attenuate abnormal protein–copper interactions in Alzheimer's and Huntington's disease where copper-modulating therapies are currently advancing through clinical trials [94]. No controlled clinical trials of copper modifying drugs have been reported in Parkinson's disease patients and copper supplementation treatments used in disorders of global copper deficit, such as Menkes disease and copper deficiency mylopathy, may be unsuitable as the identified copper deficit is highly localized within the brain and a copper supplementation approach risks peripheral copper overload, the potential dangers of which are seen in Wilson's disease [34,95], as well as possibly increasing central deposition of α-synuclein. Nevertheless model systems data support the hypothesis that restoration of the regional copper deficit in Parkinson's disease may represent a novel target for neuroprotective treatment of this disorder.

The copper-delivery compound Cu2+ complex of diacetylbis(4-methylthiosemicarbazone), [Cu2+(atsm)] [96], is neuroprotective in four different animal models of Parkinson's disease [97]. A specific role for copper in the observed beneficial effects which, in addition to reduced nigral cell loss, included improvements in motor and cognition functions and dopamine metabolism [96], is yet to be demonstrated but Cu2+(atsm) and the related compound Cu2+(gtsm) stimulate neurite elongation in cell models [98], a neurogenerative action suggested to be associated with increased copper bioavailability [98]. In this regard, it is interesting that Cu2+(atsm) accumulates within the striatum of Parkinson's disease patients, an area of progressive synapse loss, in a manner positively correlated with disease stage [99], although current imaging techniques in live patients are not sensitive enough to detect the cellular location of this accumulation. Further, Cu2+(atsm) also scavenges reactive nitrogen radicals and thus in the Parkinson's disease brain may have the additional benefit of inhibiting α-synuclein aggregation induced by nitrosative stress [97]. Considered together, the effectiveness of Cu2+(atsm) at reducing parkinsonian symptoms and substantia nigra dopaminergic cell loss suggests Cu2+(atsm) as a potential candidate for the treatment of Parkinson's disease although the mechanism/s of any neuroprotective effects remain to be elucidated.

The marked but highly localized deficiency of copper in vulnerable brain regions in Parkinson's disease suggest that, rather than simply supplementing brain copper, an approach that redistributes brain copper may be more suitable. This approach has already been used in the development of potential protective treatments for other neurodegenerative disorders in which highly localized metal dyshomoeostasis occurs [94]. The metal protein attenuating compounds (MPACs) clioquinol (PBT1) and PBT2 have been investigated for their effects on brain copper levels and their potential for treatment of Parkinson's disease. Clioquinol is a hydroxyquinoline ionophore originally used to treat fungal infections which is thought to redistribute copper from the extracellular to the intracellular space, without altering total brain copper concentrations, although it also binds both zinc and iron [100], and thus is likely not to act specifically on tissue concentrations of copper alone. Initial trials of clioquinol for treatment of Alzheimer's disease were promising, but Phase 2 trials of this compound in Alzheimer's disease were later abandoned due to problems with large scale manufacture, including the generation of toxic byproducts and the high costs associated with purification [101]. Subsequent development of PBT2, a second-generation 8-hydroxyquinoline with greater solubility than clioquinol and increased blood–brain barrier permeability, re-stimulated interest in these compounds. A 12-week Phase 2 trial investigating the safety and efficacy of PBT2 in patients with early Alzheimer's disease reported that PBT2 significantly lowered CSF levels of Aβ42, and improved executive function [102,103]. Based on in vitro studies, these benefits were suggested to result from increased cellular metal ion availability and enhanced activation of neuroprotective cell signalling pathways [104106]. Completion of a Phase 2 safety and efficacy study of PBT2 in patients with early to mid-stage Huntington's disease recently reported some modest effects on executive function with larger studies required for confirmation [107].

Although clinical trials of these compounds for Parkinson's disease have not yet been attempted, preclinical studies of clioquinol report neuroprotective properties. In the 6-hydroxydopamine Parkinson's mouse model, oral administration of clioquinol commencing on the day of lesion significantly reduced the severity of substantia nigra neuronal loss [108]. Further, in the MPTP mouse model, long-term pre-treatment with clioquinol significantly reduced substantia nigra neuronal cell loss following the lesion [109]. The effects of PBT2 have not yet been reported in preclinical models of Parkinson's disease, but data from clioquinol studies suggest it may also hold promise for the treatment of Parkinson's disease. Furthermore, another MPAC PBT434 which exhibits a higher affinity for copper than PBT2 is in preclinical development for Parkinson's disease [110] and is reported to protect nigrostriatal dopaminergic circuitry, preserve motor function and prevent α-synuclein accumulation in a number of animal models of Parkinson's disease [111].

CONCLUSION

A body of literature demonstrates decreased cellular copper levels and disrupted copper pathways in Parkinson's disease, with functional consequences for antioxidant function and brain cell health. Our understanding of the role of copper in the human brain and interactions between copper and proteins involved in Parkinson's disease pathogenesis has improved significantly over the past decade, however much remains unknown. Nonetheless, copper-modulating therapies are advancing through clinical trials for Alzheimer's and Huntington's disease and data from model systems suggest that such an approach is also likely to be beneficial in Parkinson's disease. The search for treatments capable of correcting brain copper dyshomoeostasis in Parkinson's disease has just begun. This is an exciting time for neuroscientists and neurologists as basic metals and protein research begins to translate into therapeutic strategies with real potential as disease modifying approaches for Parkinson's disease.

Abbreviations

     
  • CCS

    copper chaperone for SOD1

  •  
  • COX

    cytochrome c oxidase

  •  
  • CSF

    cerebrospinal fluid

  •  
  • MPAC

    metal protein attenuating compound

  •  
  • MPTP

    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

  •  
  • SOD1

    superoxide dismutase 1

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