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Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples


Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.


As a transition metal that can exist in several valencies, and that can bind up to six ligands, iron is an important component of industrial catalysts in the chemical industry (Hagen 2006), especially for redox reactions. Its catalysis of specific reactions requires rather exact architectures at the catalytic centre, and indeed much of the art and science of catalyst production involves determining and synthesising them. Nearly half of all enzymes are metalloproteins (Waldron et al. 2009), and iron is also of considerable importance in biology as a component of all kinds of metalloproteins (Andreini et al. 2008, 2009) from haemoglobin to cytochromes, as well as in the directed evolution of novel enzyme activities (Pordea and Ward 2008; Que and Tolman 2008; Turner 2009). When serving in enzymes, the iron is normally safely liganded, and any reactions catalysed are usually fairly specific. However, as is widely recognised, iron can also have a dark side (Kell 2009a), in that when it is not properly liganded (Graf et al. 1984), and in the ferrous form, it can react with hydrogen peroxide (produced by mitochondria (e.g. Brennan and Kantorow 2009; Fato et al. 2008; Orrenius et al. 2007) or (per)oxidases (Bedard and Krause 2007; Cave et al. 2006) via the Fenton reaction (Goldstein et al. 1993; Kruszewski 2003; Toyokuni 2002; Wardman and Candeias 1996; Winterbourn 1995), leading to the very reactive and damaging hydroxyl radical (OH)

Fig. 1
figure 1

The Haber-Weiss and Fenton reactions combine using poorly liganded iron in a catalytic cycle to produce the very damaging hydroxyl radical. Poorly liganded iron can also be liberated via the destruction of haem and other iron-containing substances. Peroxynitrite anion (ONOO) is produced by the reaction of superoxide and nitric oxide (NO) which when protonated (pH ca 6.5–6.8) decomposes to OH and NO2

Fig. 2
figure 2

Some small molecules that are derived from the oxidative attack of hydroxyl and other radicals on cellular macromolecules and that can act as biomarkers of oxidative stress, including that mediated by iron

Fig. 3
figure 3

Very strong relationship between serum ferritin concentrations and urinary concentrations of the DNA damage/oxidative stress marker 8-hydroxy-2′-deoxyguanosine. Data are replotted from Fig. 1 of Hori et al. (2010)

Fig. 4
figure 4

A mind map (Buzan 2002) setting out the structure of this review. To read this start at “1 o’clock” and move outwards and clockwise

Fig. 5
figure 5

Some of the interactions between the prion protein in its two main conformations, reactive oxygen species and iron dysregulation. This diagram is based on Fig. 12 of (Singh et al. 2010b), and illustrates in particular the autocatalytic nature of the ROS- and iron-dependent conversion of PrPC to PrPSc and the neurotoxicity of the latter

Fig. 6
figure 6

Iron catalyses the formation of the hydroxyl radical (and thence other kinds of ROS) that can react with proteins and lipids to denature them, leading to insoluble plaques and other fibrotic structures that can themselves bind/entrap the iron that caused their formation. This bound iron can cause further hydroxyl radical formation such that the process is autocatalytic. Eventually this overwhelms cellular defences, leading to cell death (with further release of iron)

Fig. 7
figure 7

Large (17-fold) accumulation of EPR-detectable iron in atherosclerotic plaques relative to healthy non-atherosclerotic (‘intima’) controls. The difference is highly significant (P = 0.0001). Data are replotted from those in Fig. 1b of Stadler et al. (2004)

Fig. 8
figure 8

The major events accompanying sepsis and the Systemic Inflammatory Response Syndrome. Note in particular the positive feedback by which the release of pro-inflammatory cytokines and ROSs leads to the release of poorly liganded iron (e.g. from ferritin and haem) that causes the release of further inflammatory cytokines and ROSs. In principle, iron chelators could interfere with this vicious cycle

Fig. 9
figure 9

A diagram, based very loosely on the narrative in (Kohanski et al. 2007), illustrating how the autocatalytic activity of the reactions of superoxide, peroxide and the hydroxyl radical involving poorly liganded iron can exert a positive feedback leading to the death of cells

Fig. 10
figure 10

‘Bow-tie’ models of cellular networks. There are many examples of cellular networks in which a large variety of possible initial events leads to complex sequelae, but these are mediated via a comparatively small number of ‘intermediate’ reactions. While in the present case it is suggested that these in part involve complex positive feedbacks, the general ‘bow-tie’ idea does allow one to recognise that despite the many different possible inputs, a broadly unitary kind of mechanism of action—here involving iron dysregulation—can reasonably be invoked to explain the multiple causes that can lead to cell death and destruction

Fig. 11
figure 11

The three main iron chelators approved for clinical use

Fig. 12
figure 12

The extent of cell damage caused by the unliganded iron-catalysed production of ROSs and RNSs is determined by many factors, some of which promote and some of which act against it. While the existence of hormesis (see text) means that the see-saw illustrated here is an imperfect metaphor, the diagram serves to illustrate the complexity of the problem and the need for a systems biology approach to its solution

Fig. 13
figure 13

The steady-state concentrations of a molecule depend on the rates of production and removal of the molecule in question. Both lowering creation and increasing removal represents a particularly effective strategy relative to doing just one of these alone. Thus if C is the hydroxyl radical we can lower its concentration by decreasing A and/or B and by increasing the rates of the reaction to D and E. The latter (decrease of concentration of C) may sometimes better be effected by increasing the activities of enzymes yet further downstream

Fig. 14
figure 14

The relationship between ‘forward’ and ‘inverse’ methods of systems biology. The comparison of two ‘inverse’ systems (one a control and one treated with a toxin) in terms of the estimation of which parameters have changed most allows one to infer the sites or modes of action of that toxin [In a related manner we also discriminate forward and reverse genetics, including chemical genetics (Kell 2006a, b)].

$$ \hbox{Fe}(\hbox{II})+\hbox{H}_2\hbox{O}_2 \rightarrow \hbox{Fe}(\hbox{III})+\hbox{OH}^{-}+\hbox{OH}^{\bullet} $$

Superoxide (also produced by mitochondria) can react with ferric iron in the Haber-Weiss reaction (Kehrer 2000) to produce Fe(II) again, thereby effecting redox cycling of the iron (Fig. 1):

$$ \hbox{O}_2^{\bullet -}+\hbox{Fe}(\hbox{III})\rightarrow \hbox{O}_2+\hbox{Fe}(\hbox{II}) $$

Ascorbate (vitamin C) can also replace \( \hbox{O}_2^{\bullet -} \) for reducing the Fe(III) to Fe(II) (Hershko and Weatherall 1988), as can other reducing agents, and indeed too low a redox poise leads to DNA damage (e.g. Li and Marbán 2010; Seifried et al. 2007).

The hydroxyl radical is exceptionally reactive and damaging to cellular components, and, for instance, can liberate further Fe(II) from iron-sulphur centres and other iron-containing compounds such as ferritin (Arosio et al. 2009), thereby driving reaction (1) in an autocatalytic, runaway kind of reaction. This kind of phenomenon has the potential to overwhelm any kinds of attempts at repair, and inflammation and oxidative stress are the hallmarks of each of the conditions I summarise. Related reactions include peroxynitrite production (from the reaction of NO and superoxide) (Babior 2000; Beckman et al. 1990; Beckman and Koppenol 1996; Goldstein and Merényi 2008; Koppenol et al. 1992; Murphy et al. 1998; Pacher et al. 2007; Pavlovic and Santaniello 2007; Pryor and Squadrito 1995; Radi et al. 2001, 2002; Rubbo and O’Donnell 2005; Rubbo et al. 2009; Smith et al. 1997b; Squadrito and Pryor 1998; Szabo 1996; Szabó et al. 2007; Torreilles et al. 1999; White et al. 1994; Zimmet and Hare 2006). These can lead to nitrotyrosine (Beckman 1996; Goldstein and Merényi 2008; Herce-Pagliai et al. 1998) (a reaction catalysed by poorly liganded iron, Beckman et al. 1992), or nitro-fatty acid (Aslan et al. 2001; O’Donnell and Freeman 2001) production or protein cysteine nitrosylation (Lancaster 2008; Landino 2008; Vaz and Augusto 2008) that can provide a means of their detection downstream. Some of these are shown in Fig. 2. A key point here is that despite the widespread and uncritical use of the term ROS to describe any ‘Reactive Oxygen Species’, most such as superoxide and peroxide are not terribly reactive, in contrast to the hydroxyl radical (and peroxynitrite) which is, and unliganded iron is required for hydroxyl radical production in the Fenton reaction. Hence the focus on unliganded iron rather than the more nebulous ROSs, albeit that (su)peroxide is necessarily involved.

Clearly the occurrence of these activities leads to the (more or less irreversible) formation of a variety of substances that can act as biomarkers of these activities (Kell 2009a), and such oxidised compounds are represented by both small and macro-molecules. For instance, 8-hydroxy-2′-deoxyguanosine (8-OHdG) (ChEBI 40304) also referred to as its tautomer 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) (HMDB03333) is produced when the hydroxyl radical reacts with DNA and damages it (e.g. Bal and Kasprzak 2002; Burrows and Muller 1998; Cooke et al. 2003, 2008; Lloyd et al. 1998; Loft and Poulsen 1996; Orhan et al. 2004; Shi et al. 2003; Toyokuni and Sagripanti 1996; Valavanidis et al. 2009; Valko et al. 2005), and body-iron status correlates rather strongly with its production or urinary excretion (Agarwal et al. 2004; Broedbaek et al. 2009; Fujita et al. 2007a, 2009; Gackowski et al. 2002; Hori et al. 2010; Kang et al. 1998; Kuo et al. 2008; Maruyama et al. 2007; Nakano et al. 2003; Toyokuni and Sagripanti 1996; Tuomainen et al. 2007; Valavanidis et al. 2005). The data in (Hori et al. 2010) relating urinary 8-OHdG levels to serum ferritin concentrations are particularly striking, and I have digitised them (cf. Pettifer et al. 2009 for pointers to automated ways of doing this in the future) and replotted some of them in Fig. 3.

Ferritin levels (a common measure of body iron stores) are also widely associated with disease development/ severity/ poor outcomes (e.g. Alissa et al. 2007; Armand et al. 2007; Bartzokis et al. 2007; Braun et al. 2004; Bugianesi et al. 2004; Chen et al. 2006; Choi et al. 2005; Double et al. 2000; Fargion et al. 2001; Fernández-Real et al. 2002; Ford and Cogswell 1999; Forouhi et al. 2007; He et al. 2007; Hubel et al. 2004; Ishizaka et al. 2005; Jehn et al. 2004, 2007; Kaur et al. 2007; Kiechl et al. 1997; Lee et al. 2006f; Lim et al. 2001; Rayman et al. 2002; Rouault 2006; Salonen et al. 1992; Sheth and Brittenham 2000; Tuomainen et al. 1998; Valenti et al. 2007; Wilson et al. 2003; You et al. 2003; You and Wang 2005) (Adamkiewicz et al. 2009; Baune et al. 2010; Busca et al. 2010; DePalma et al. 2010; Ferrara et al. 2009; Ferrucci et al. 2010; Gamberini et al. 2008; Goodall et al. 2008; Inati et al. 2010; Kaysen 2009; Knovich et al. 2009; Kolberg et al. 2009; Lecube et al. 2008; Lim et al. 2010; Mateo-Gallego et al. 2010; McNeill et al. 2008; Menke et al. 2009; Qureshi et al. 2008; Rajpathak et al. 2009; Sharifi et al. 2008; Skinner et al. 2010; Song et al. 2009; Storey et al. 2009; Sun et al. 2008; Tsimikas et al. 2009; Valenti et al. 2010; Walker et al. 2010; Wang et al. 2010b; Yoneda et al. 2010; Zandman-Goddard and Shoenfeld 2008), though note that most assays are for the protein itself, and not for the full molecule including any iron that it may sequester effectively (Balla et al. 1992; Hintze and Theil 2006; Theil 2007) or otherwise.

Although iron is most commonly bivalent, Fe(II), or trivalent, Fe(III), this simple statement does not remotely cover the relevant chemistry and speciation that are necessary to recognise what forms of ‘iron’ may be safe and which are likely to catalyse damaging reactions. The first issue is that at neutral pH Fe(III) is more or less insoluble, and in aerobic environments it is necessary to chelate the otherwise ‘free’ Fe(III) with appropriate chelators or siderophores (especially for microbes, e.g. Andrews et al. 2003; Barry and Challis 2009; Cornelis and Andrews 2010; de Carvalho and Fernandes 2010; Haas et al. 2008; Johnson 2008; Miethke and Marahiel 2007; Raymond et al. 2003; Sandy and Butler 2009; Wandersman and Delepelaire 2004; Winkelmann 2002). These siderophores—secreted as are other bacterial pheromones (Kell et al. 1995)—typically have extremely tight binding constants (K f > 1030, e.g. Clifton et al. 2009; Loomis and Raymond 1991) and can solubilise and sequester iron such that it can be internalised via suitable transporter molecules within the plasma membrane (Stintzi et al. 2000).

Iron contains up to six individual chelation sites, arranged octahedrally, and ligands can typically satisfy them partially (i.e. some ligands are bidentate or tridentate and need three or two molecules for full liganding/activity) or fully i.e. are hexadentate. Since iron cannot be transmuted into any other substance, the only way to stop the damaging activity of free or partially liganded ‘iron’ is to ensure that all of its six possible liganding sites are satisfied , whether by endogenous chelators or those added from the diet or as pharmaceuticals. Put another way, it is not simply enough to know that ‘iron’ is present at an adequate level but that it is available in a suitably liganded form. Anaemia can be caused by poor liganding as well as by an actual shortage of ‘iron’ itself. Note too that partial chelation in the presence of an antioxidant agent such as ascorbate (vitamin C) can in fact make ascorbate (or other reducing agent) act as a pro-oxidant and thus actually promote the production of OH radicals in the presence of inappropriately or inadequately liganded Fe(II) (Allen and Cornforth 2009; Fábián and Csordás 2003; Halliwell 2009; Hininger et al. 2005; Lachili et al. 2001; Long et al. 2000; Miller et al. 1990; Reif 1992; Sugihara et al. 1999). This very likely explains the often and indeed surprisingly disappointing clinical results obtained when using antioxidants alone (Bjelakovic et al. 2008; Giustarini et al. 2009; Kell 2009a; Miller et al. 2005).

The above facts are well known (e.g. Halliwell and Gutteridge 2006; Weinberg 2004), and I discussed them at length in a recent and wide-ranging review (Kell 2009a). My purpose here is to look more closely at the evidence that they are part of the sequelae of a number of predispositions to cellular and organismal death (whether by necrosis or apoptosis) that follow from a large variety of initial ‘insults’ or distal causes, whether of genetic or environmental origin (or both). While, as a systems property, many other cellular processes contribute measurably to any specific activity, I suggest, in all the disparate cases I review, that it is the binding of poorly liganded iron (mainly bivalent) to inappropriate cellular structures that serves to generate this catalytic activity, albeit that the overall manifestations may differ at a physiological level, and I here review what evidence is available. This basic suggestion can be tested explicitly more or less easily. I suggest further that it is this ongoing, autocatalytic activity based on positive feedback that is responsible for the really large-scale damage, leading to organismal death, that can occur in affected cells, tissues, organs and organisms. This analysis also suggests an important role for iron chelation as part of combination approaches in the acute and chronic therapy of these conditions. An overview of this article is given as a Mind Map (Buzan 2002) in Fig. 4.

Note that I do recognise that other transition and polyvalent metal ions (Aln+, Crn+, Cun+, Mnn+, Sen+, Znn+ etc.) may also contribute to the kinds of process I describe. However, for reasons of simplicity, focus, and because of the natural abundance of this metal in biological systems, it is ‘iron’ on which I shall concentrate. As previously (Kell 2009a), I use the term ‘iron’ to include iron of any valencies or speciation, unless specified otherwise.

Since the role of iron is obvious in cases of primary diseases of iron overload, such as hereditary haemochromatosis (e.g. Camaschella and Merlini 2005; Ellervik et al. 2007; Gan et al. 2010; Limdi and Crampton 2004; Mair and Weiss 2009; Marx 2002; McLaren and Gordeuk 2009; Pantopoulos 2008; Papanikolaou and Pantopoulos 2005; Pietrangelo 2006; Weiss 2010), thalassaemias (e.g. Borgna-Pignatti et al. 2005; Camaschella and Merlini 2005; Cao and Galanello 2010; Cohen et al. 2004; Gattermann 2009; Lam et al. 2008; Li et al. 2010; Mohkam et al. 2008; Peng et al. 2008; Taher et al. 2010; Vichinsky et al. 2005) and myelodysplastic syndrome (e.g. Cazzola et al. 2008; Cuijpers et al. 2010; Dreyfus 2008; Gattermann 2008; Greenberg 2006; Greenberg et al. 2008; Jabbour et al. 2009; Jädersten and Hellström-Lindberg 2010; Leitch 2007; Mahesh et al. 2008; Malcovati 2009; Porter et al. 2008; Wimazal et al. 2009), I largely ignore this literature. However, I recognise that the sequelae of iron overload, especially various kinds of organ failure, share many similarities to those I describe below, consistent with the role of iron in these other cases where its involvement has been less widely recognised. Clearly the commonality of any specific effect with those of known iron overload (Dever et al. 2010) might give strong hints for the involvement of iron in specific toxicological processes.

The literature survey at the time of initial submission for review extended to 14 June, 2010.

To start our survey, we look at the consequences of an acute cerebral infarction or stroke.


Stroke is a term used to describe the destruction of brain cells, typically following a temporary blockage in blood flow (ischaemia-reperfusion injury) or an intra-cranial haemorrhage. The extent of damage varies considerably, and can be exacerbated because affected cells can release inflammatory cytokines that activate other cells in a similar way, providing a positive autocatalytic effect and leading to spreading of the damage. It is this secondary spreading that is especially damaging, but because it is slower (4–7days), it also affords the opportunity for therapeutic intervention (Qureshi et al. 2009). It is now clear that iron is intimately involved (Armengou and Davalos 2002; Bailey et al. 2006; Bishop and Robinson 2001; Chang et al. 2005; Dávalos, et al. 1994; Demougeot et al. 2004; Ferro and Dávalos 2006; Garoufi et al. 2006; Gillum et al. 1996; Lee et al. 2006e; Marniemi et al. 2005; Mascitelli and Pezzetta 2006; Mehta et al. 2004; Mu et al. 2005; Nakamura et al. 2006; Saxena et al. 2005; Selim and Ratan 2004; Switzer et al. 2006; Wagner et al. 2003; Wu et al. 2003; Zuliani et al. 2006; Adams 2007; Altamura et al. 2009; Assenza et al. 2009; Basak et al. 2008; Bosomtwi et al. 2008; Carbonell and Rama 2007; Cho et al. 2007; Ekblom et al. 2007; Hanson et al. 2009; Heckl 2007; Helal 2008; Jolkkonen et al. 2007; Justicia et al. 2008; Kaushal and Schlichter 2008; Kim et al. 2008a; Kobayashi et al. 2008; Lou et al. 2009; Maguire et al. 2007; Mazumdar et al. 2007; Mehdiratta et al. 2008; Millan et al. 2007, 2008; Millerot-Serrurot et al. 2008; Nighoghossian et al. 2008; O’Rourke et al. 2008; Ratan et al. 2008; Ross and Meschia 2009; Saleh et al. 2007; Santhosh et al. 2009; Verduzco and Nathan 2009; Walters and Rye 2009; Weng et al. 2008), whether by release from (ferritin in) cells or from the haem of haemoglobin. Iron chelators have thus shown promise in decreasing the sequelae of an initial stroke-inducing event (Demougeot et al. 2004; Ferro and Dávalos 2006; Hurn et al. 1995; Kompala et al. 1986; Mu et al. 2005; Patt et al. 1990; Prass et al. 2002; Selim and Ratan 2004; Soloniuk et al. 1992; White et al. 1988; Chen-Roetling et al. 2009; Gu et al. 2009; Hanson et al. 2009; Hua et al. 2008; Mazumdar et al. 2007; Méthy et al. 2008; Millerot-Serrurot et al. 2008; Mirre et al. 2010; Okauchi et al. 2009, 2010; Ratan et al. 2008; Robinson et al. 2009; Selim 2009; Verduzco and Nathan 2009), providing further evidence for the primary importance of iron in causing injury.

While stroke is a sudden occurrence, albeit with secondary consequences, a number of neurodegenerative diseases are rather more long term in their development, and we now look at several, each of which is seen to involve iron intimately.

Huntington’s disease

The pathology of HD reveals striking neurodegeneration in the corpus striatum and shrinkage of the brain, leading to its most prominent manifestation, viz. movement disorders or chorea (Bhidayasiri and Truong 2004). Huntington’s disease occurs via the addition of trinucleotide CAG repeats within exon 1 of the relevant gene, encoding (poly)glutamine (polyQ) repeats in the huntingtin protein (htt) and leading to a gain of (toxic) function (Bauer and Nukina 2009; Gusella and MacDonald 2000; Imarisio et al. 2008; Quintanilla and Johnson 2009). The number of these repeats determines both the time of onset of observable disease (more repeats meaning earlier onset) (Perutz and Windle 2001; Ross 1995; Walters and Murphy 2009), accounting for 70% of the variance (Imarisio et al. 2008), and the disease severity, implying that it is indeed the polyglutamines themselves that are the chief culprits. Some of the polyQ-containing huntingtin proteins can also aggregate to form inclusion bodies, and aggregation and neurodegeneration can in part be related (Chopra et al. 2007; Cowan et al. 2003; Michalik and Van Broeckhoven 2003; Nagai et al. 2003; Wang et al. 2005, 2009; Zhang et al. 2005a). Now the evidence for the involvement of poorly liganded iron in a wide variety of neurodegenerative diseases is overwhelming (e.g. Benarroch 2009; Bishop et al. 2010a; Brown 2009a; Friedman et al. 2007; Jellinger 1999; Ke and Qian 2003; Kell 2009a; Lee et al. 2006a; Perez and Franz 2010; Thompson et al. 2001; Youdim et al. 2004b; Zecca et al. 2004), and the question arises as to whether huntingtin (or, more likely, its degradation fragments), containing these polyQ tracts, can catalyse oxidative stress and/or hydroxyl formation directly. In an important paper, Firdaus et al. (Firdaus et al. 2006) show that that huntingtin inclusion bodies act as centres of oxidative stress and that partially purified inclusion bodies contain large amounts of oxidised proteins. Iron metabolism is deranged in gene knockdown models of Huntington’s (Henshall et al. 2009; Lumsden et al. 2007), and experiments with the iron chelator deferroxamine revealed that the oxidation, localisation and structural organisation of the inclusion bodies formed by mutant htt were indeed irondependent. They did not demonstrate the ability of these inclusion bodies to catalyse hydroxyl formation, but this could easily be shown using specific assays, such as the hydroxylation of suitable aromatics (e.g. Grootveld and Halliwell 1986; Halliwell and Gutteridge 2006; Thomas et al. 2009a). The iron chelator clioquinol is also protective (Nguyen et al. 2005).

Parkinson’s disease

Parkinson’s disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra part of the brain and is characterised in particular by the presence of intracytoplasmic inclusions from protein aggregates called Lewy bodies (LB) and at the physiological level by a variety of movement disorders (e.g. Singh et al. 2007). It is strongly linked with oxidative stress (e.g. Alam et al. 1997; Büeler 2009; Jenner 2003; Jenner and Olanow 1996; Kidd 2000; Mandel et al. 2003; Olivares et al. 2009; Seet et al. 2010; Van Laar and Berman 2009; Zhang et al. 1999). Again (e.g. Berg et al. 2001; Bharath et al. 2002; Buchanan et al. 2002; Bush 2000; Castellani et al. 2002; Double et al. 2000; Good et al. 1998; Gotz et al. 2004; Hirsch and Faucheux 1998; Jellinger 1999; Johnson 2000; Olanow and Arendash 1994; Ostrerova-Golts et al. 2000; Sofic et al. 1991; Wolozin and Golts 2002; Altamura and Muckenthaler 2009; Andersen 2004; Barapatre et al. 2010; Baudrexel et al. 2010; Becker 2010; Becker et al. 2010a, b; Berg 2006, 2007; Berg and Hochstrasser 2006; Berg et al. 2006, 2008; Brar et al. 2009; Brown 2009b; Crichton and Ward 2006; Fasano et al. 2006; Friedman et al. 2007, 2009; Ghosh et al. 2010; Hirsch 2009; Jellinger 2009; Jimenez-Del-Rio et al. 2010; Kaur and Andersen 2004; Lee and Andersen 2010; Levenson 2003; Mandemakers et al. 2007; Matusch et al. 2010; Oakley et al. 2007; Salvador 2010; Shi et al. 2010; Wayne Martin 2009; Wypijewska et al. 2010; Yeager and Coleman 2010; Zecca et al. 2004; Zhang et al. 2005, 2010b)—there is overwhelming evidence for the involvement of iron in this neurodegeneration. Why these dopaminergic neurons are especially susceptible is not entirely clear, although dopamine is capable of reacting with iron directly to form a toxic complex (Arreguin et al. 2009; Paris et al. 2005) that probably itself catalyses hydroxyl formation. Iron chelators inhibit these inimical processes (Gal et al. 2006; Perez et al. 2008; Xu et al. 2008; Youdim et al. 2004a, b; Zheng et al. 2005), including (Kaur et al. 2003; Reznichenko et al. 2010; Youdim 2003) in the case of a Parkinson-like disease induced (Blum et al. 2001; Choi et al. 2009; Gal et al. 2009; Yokoyama et al. 2008) by 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) (ChEBI 17963). The Lewy bodies contain lipid and a variety of proteins, including ubiquitin, neurofilament, various proteasomal elements and α-synuclein, which may be oxidatively modified (Double et al. 2008). Ferric iron may itself catalyse the formation of α-synuclein oligomers (Brown 2009a; Hillmer et al. 2009; Peng et al. 2010), and copper may also be involved (Wang et al. 2010c).

Melanins are polymers of polyphenols, especially of L-dopamine, although neuromelanin, which also contains oxidatively polymerised dopamine or noradrenaline with the possible involvement of cysteinylderivatives (Fedorow et al. 2005), is of special interest here. The substantia nigra also contains a substantial amount of the dark, insoluble polymeric pigment neuromelanin, and this has been shown directly to bind (and release) iron in high amounts (Double et al. 2003a, b; Fasano et al. 2006; Faucheux et al. 2003; Gerlach et al. 2003, 2008; Shamoto-Nagai et al. 2006), and thereby to produce an iron-loaded form that seems to serve as a reservoir catalysing (hydroxyl) radical formation and whose amounts correlate with PD. In this case, the in vitro experiments have been done, and incubation of human neuromelanin with iron in vitro stimulates oxidative tissue damage (Ben-Shachar et al. 1991; Double et al. 2003a; Gerlach et al. 2008).

Another dark pigment commonly observed in PD patients (and other neurodegenerative diseases) is lipofuscin (Double et al. 2008; Jung et al. 2007; Terman and Brunk 2004). Lipofuscin too consists of lipids and oxidised proteins, often crosslinked by oxidised lipid derivatives such as (E)-4-hydroxy-non-2-enal (ChEBI 58968) and can adsorb high contents of metals (including iron) of up to 2% by weight (Jung et al. 2007). It is typically formed in lysosomes from degrading mitochondria (Terman et al. 2006a), themselves rich in metalloproteins, and the inability of cells to degrade it means that (purportedly) non-dividing cells (such as brain tissue) simply accumulate it as cells age (Terman and Brunk 2004, 2006). This arguably explains why non- or rarely-dividing tissues such as brain tissues are particularly susceptible, though note the important and increasing evidence (e.g. Abrous et al. 2005; Christie and Cameron 2006; Demir et al. 2009; Fuchs and Gould 2000; Götz and Huttner 2005; Gould 2007; Imayoshi et al. 2009; Leuner et al. 2007; Lledo et al. 2006; Ohnuma and Harris 2003; Taupin 2007; Zhao et al. 2008) for considerable turnover—neurogenesis—in at least some regions of the brain. The autocatalytic nature of the process—lipofuscin loaded with iron catalyses more lipofuscin production—is especially dangerous and can (as one would predict) be inhibited using appropriate iron chelators (Persson et al. 2003). Iron chelation also assists neurogenesis (Nowicki et al. 2009).

Thus, as with Huntington’s, Parkinson’s disease is clearly characterised by all the hallmarks of hyperactive hydroxyl radical generation, leading to cell death and destruction, in this case mainly, it would seem (Chen et al. 2007; Chiueh et al. 2000; Ekshyyan and Aw 2004; Jellinger 2002; Jenner 2003; Jenner and Olanow 1996; Kermer et al. 2004; Levenson 2005; Loh et al. 2006; Mandel et al. 2005; Mattson 2006; Okouchi et al. 2007; Xu et al. 2008a; Yasuda and Mochizuki 2010), by apoptosis.

Gaucher’s disease

Gaucher’s disease is an autosomally recessive inborn error of metabolism due to deficiency of a lysosomal enzyme, glucocerebrosidase (GBA), resulting in the accumulation of glucocerebroside in large macrophages throughout the reticuloendothelial system, leading to various neuronopathies. Given that the lysosome is the site of most labile iron in the cell (Fakih et al. 2008; Gorria et al. 2008; Kurz et al. 2004, 2008a, b; Persson 2005; Tenopoulou et al. 2007; Terman et al. 2006b; Yu et al. 2003), it is also of interest that there is an increased frequency of mutations in the gene encoding GBA among patients with Parkinson’s disease (e.g. Aharon-Peretz et al. 2004; Clark et al. 2007; Gan-Or et al. 2008; Lwin et al. 2004), and vice versa (Sidransky et al. 2009). Iron dysregulation is also well established in Gaucher’s disease (Finch et al. 1986; Lee et al. 1967, 1977; Lorber 1960, 1970; Morgan et al. 1983; Schiano et al. 1993; Weisberger et al. 2004). This recognition of the role of iron dysregulation in Gaucher’s disease may offer novel therapeutic approaches.

Alzheimer’s disease

Alzheimer’s disease (AD), the commonest of the neurodegenerative disease of ageing, shares many similarities with Huntington’s and Parkinson’s diseases, not least the extensive evidence for the role of oxidative stress (e.g. Butterfield et al. 2007; Christen 2000; DiMauro and Schon 2008; Good et al. 1996; Milton 2004; Miranda et al. 2000; Moreira et al. 2009; Nunomura et al. 2001, 2006; Reddy and Beal 2008; Reddy et al. 2009; Rottkamp et al. 2000; Smith et al. 1996, 2000; Zhu et al. 2007) and of iron (e.g. Adlard and Bush 2006; Avramovich-Tirosh et al. 2007a; Becker et al. 2010b; Bishop et al. 2002; Blázquez et al. 2007; Bolognin et al. 2009b; Brar et al. 2009; Bush 2000, 2003, 2008; Casadesus et al. 2004; Castellani et al. 2007; Collingwood and Dobson 2006; Collingwood et al. 2008; Connor and Lee 2006; Ding et al. 2009; Doraiswamy and Finefrock 2004; Gerlach et al. 1994; Good et al. 1996; Hegde et al. 2009; Honda et al. 2004; Jellinger et al. 1990; Jellinger 2009; Kala et al. 1996; Lehmann et al. 2006; LeVine 1997; Lovell et al. 1998; Malecki and Connor 2002; Mandel et al. 2007; Markesbery 1997; Markesbery and Lovell 1998; Mascitelli et al. 2009; Olanow and Arendash 1994; Ong and Farooqui 2005; Quintana et al. 2006; Rival et al. 2009; Robson et al. 2004; Silvestri and Camaschella 2008; Smith et al. 1997a, 2010; Tabner et al. 2005; Thomas and Jankovic 2004; Thompson et al. 2001; Valko et al. 2005; Zatta et al. 2009; Zecca et al. 2004; Zheng et al. 2005). It is especially noteworthy that iron correlates with disease severity as measured by cognitive ability (Ding et al. 2009; Gómez Ravetti et al. 2010; Grossi et al. 2009; Lavados et al. 2008; Perez et al. 2010; Smith et al. 2010). AD is characterized by the loss of neurons in the cognitive centres of the brain and by the presence of two separate pathological lesions, extracellular β-amyloid (Aβ) plaques (e.g. Dong et al. 2003; Scott and Orvig 2009) and neurofibrillary tangles within neurons (Shcherbatykh and Carpenter 2007).

Again, there is evidence that insoluble polymers (fibrillary tangles) of proteins such as the β-amyloid can bind iron (Castellani et al. 2007; Dickens and Franz 2010; Exley 2006; Good et al. 1992; Jiang et al. 2009; Mancino et al. 2009; Rival et al. 2009; Sayre et al. 2000b; Smith et al. 2007) and thereby act in an autocatalytic manner to promote further radical production and oxidative stress. There is a also relationship between the ability to bind haem and neurotoxicity (Atamna 2009; Atamna et al. 2009), and (HFE) mutations that cause haemochromatosis increase the susceptibility to AD (Bartzokis et al. 2010; Candore et al. 2003; Combarros et al. 2003; Connor and Lee 2006; Haacke et al. 2005; Kauwe et al. 2010; Lleó et al. 2002; Moalem et al. 2000; Pulliam et al. 2003; Robson et al. 2004; Sampietro et al. 2001), especially when in the presence of the APOE4 allele (Pulliam et al. 2003). (HFE mutations also increase susceptibility to PD (Biasiotto et al. 2008; Dekker et al. 2003)—but cf. (Aamodt et al. 2007)—and to ALS (Ellervik et al. 2007)).

Importantly, iron chelators have been shown to ameliorate the development of fibril formation/neurodegeneration/dementia/AD (Amit et al. 2008; Avramovich-Tirosh et al. 2007a; Bandyopadhyay et al. 2006; Barnham et al. 2004; Biran et al. 2009; Bolognin et al. 2009a; Crapper McLachlan et al. 1991; Cuajungco et al. 2000; Faux et al. 2010; Finefrock et al. 2003; Liu et al. 2009b, c, 2010; Mancino et al. 2009; Mandel 2007, 2008; Reznichenko et al. 2006; Scott and Orvig 2009; Weinreb et al. 2009a; Zheng et al. 2005). Although this fact rarely appears in papers setting out therapeutic options for preventing (or at least ameliorating the progress of) AD, this already considerable literature suggests that trials using modern iron chelators would be of worth.

Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease)

ALS is another neurodegenerative disease in which iron has been strongly implicated (and thus the same kinds of mechanism as described previously) (Bush 2000; Carri et al. 2003; Cozzolino et al. 2008; Goodall et al. 2008; Jeong et al. 2009; Kasarskis et al. 1995; Mattson 2004; Migliore et al. 2005; Molfino et al. 2009; Qureshi et al. 2008; Reynolds et al. 2007; Sadrzadeh and Saffari 2004; Sayre et al. 2000a; Scott and Orvig 2009; Spasojević et al. 2010; Sutedja et al. 2007; Wang et al. 2004). Again, the clear benefits of iron chelators in mouse models (Jeong et al. 2009; Petri et al. 2007) and elsewhere (Avramovich-Tirosh et al. 2007b; Bolognin et al. 2009a) would seem to merit trials in humans known to be at risk. Long-standing associations of some forms of ALS with mutations in genes coding for superoxide dismutase 1 (e.g. Dalle-Donne 2007; Pasinelli and Brown 2006; Rosen et al. 1993; Vucic and Kiernan 2009; Wijesekera and Leigh 2009) are consistent with this, and recent genetic associations (e.g. Kwiatkowski Jr. et al. 2009; Valdmanis et al. 2009; Vance et al. 2009) include one with optineurin (Maruyama et al. 2010) that together with other evidence implies an interaction with NF-κB (see later) leading to the downstream effects of apoptotic neuronal cell death.

Friedreich’s ataxia

Friedreich’s ataxia is another neurodegenerative disease caused by the insertion of a trinucleotide repeat (or occasionally a missense mutation) in the gene encoding a protein called frataxin (Adibhatla and Hatcher 2010; Babady et al.