Review
Iron, the substantia nigra and related neurological disorders

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Abstract

Background

Iron status is higher in the substantia nigra than in other brain regions but can fluctuate as function of diet and genetics and disease. Of particular note is the compartmentalization of the iron-enrichment in this region; the pars reticulata contains higher levels of stainable iron as compared to the pars compacta. The latter area is where the dopaminergic neurons reside. How this compartmentalization impacts the interpretation of data that iron contributes to cell death as in Parkinson's disease or iron deficiency contributes to altered dopaminergic activity is unknown. Nonetheless, that iron can influence neuronal cell death and dopamine function is clear.

Methods

The mechanisms by which iron may be managed in the substantia nigra, particularly in the neuromelanin cells where minimal levels of ferritin the iron storage protein have been detected are addressed. The current approaches to detect iron in the substantia nigra are also reviewed. In addition, the potential mechanisms by which iron enrichment may occur in the substantia nigra are explored.

General Significance

This review attempts to provide a critical evaluation of the many avenues of exploration into the role of iron in one of the most iron-enriched and clinically investigated areas of the brain, the substantia nigra.

Introduction

Imaging studies indicate that levels of iron are enriched in the substantia nigra (SN) as compared to other brain regions. Magnetic resonance imaging (MRI) and transcranial sonography have been used to assess overall iron content in the SN [1], [2], [3], [4], [5]. These studies indicate that iron is increased in the SN relative to other brain regions. The imaging data are supported by histochemical staining for iron in autopsy studies in humans. Indeed, enrichment of iron in the SN is not unique to humans, as this region is also iron-rich in mice, rats, dogs and non-human primates [6].

The substantia nigra is comprised of two parts: the pars compacta (pc) and the reticulata (r). The SNpc contains the dopaminergic, neuromelanin-containing neurons along with supporting astrocytes, oligodendrocytes, and microglia. Axons from the dopaminergic neurons in this region project anteriorally to the striatum and comprise the nigrostriatal pathway. The SNr is located anatomically inferior to the SNpc and contains primarily oligodendrocytes along with astrocytes and microglia and is heavily myelinated. When the SN is stained for iron, it is the SNr that appears most prominent. At the cellular level, the oligodendrocytes stain more strongly for iron than any other cell type; which is consistent for all brain regions examined [7], [8], [9], [10], [11], [12]. Indeed the relatively strong iron staining in the SNr is consistent with previous reports that iron is more abundant in white matter than gray matter. The imaging data are consistent with the histochemical studies that the SNr is most prominent, although the absolute boundary between the SNr and SNpc is not easy to delineate in the imaging studies [1]. Immunostaining for ferritin, the iron storage protein, follows the pattern of iron staining and will be discussed later.

The iron content of the SN increases with age [2], [11], [12], [13], [14]. At birth iron levels are at their lowest, and the SN becomes iron-enriched during the late-teens to early twenties [11], [13]. Overall, the levels of iron in the SN in healthy elderly individuals are higher when compared to other areas such as the frontal cortex and basal ganglia [15]. A recent study using in-bred mouse strains found that iron concentrations in the SN can vary by as much as three times among different strains of mice [16]. Although the total range of iron concentration in the nigra among all strains tested is unaffected by gender, the concentration of iron within a particular strain of mice is usually affected by gender [16]. This gender difference in iron status of the SN may be important in response to iron deficiency and in prevalence of Parkinsonism as discussed later.

Traditional thinking about the role of iron in the SN has focused on the requirement of iron for tyrosine hydroxylase (TH) activity, because ferrous iron is a necessary cofactor for TH, the rate-limiting step in dopamine synthesis. As mentioned previously, stainable iron is not detected in the SNpc. Indeed, the SNpc is not enriched for iron relative to other brain nuclei, including the SNr, red nucleus, and deep cerebellar nuclei [5]. Nonetheless, much of what we know about the role of iron in the dopaminergic system has come from studies in which animals have been deprived of iron. This is an extensive area of research (for reviews see [20], [21]) and will be summarized here.

Iron deficiency in post-natal rats is associated with a decrease in the amount of iron in the ventral midbrain – which includes the ventral tegmental area and the substantia nigra – as compared to animals that never experienced iron deficiency [22], [23]. Levels of TH in the ventral midbrain appear to be elevated in iron-deficient animals as compared to controls [24]. This increase in TH may suggest a compartmentalization of the iron to essential functions within a cell; in this case all of the available iron is bound to TH in attempts to normalize dopamine production. Indeed, dopamine levels in iron-deficient animals are normal and extracellular dopamine is slightly elevated in an iron-deficient state [24], [25]. This observation is likely to have a significant impact on the traditional interpretation and future directions of the impact of iron deficiency on the nervous system but is beyond the scope of this review.

In rats the “critical period” for iron accumulation in the nigra occurs between post-natal days 14 and 21 [26]. Studies have shown that dietary iron inadequacy does not have a permanent effect on most biological and behavioral abnormalities if an iron sufficient diet is provided early enough in development [23], [24]. Indeed, iron replenishment to formerly iron-deficient animals can result in increased levels of iron [22], [23], provided that iron replenishment occurs within the critical time-point [23], [24], [26]. The mechanism by which the iron replenishment results in increased iron in the SN is not clear, but may not involve mobilization by transferrin because this protein is not altered in the nigra following iron deficiency [27].

The dopaminergic neurons of the SNpc project to the basal ganglia, so examination of this brain region is a strong indicator of how the dopaminergic system is altered due to iron deficiency. In iron-deficient rats, the function of DAT – the dopamine transporter that recycles dopamine from the synapse back into the pre-synaptic neuron – is decreased in both the ventral midbrain and in the caudate/putamen [22]. There appears to be general agreement in the literature that exposing rat pups to iron-deficient dams or an iron-deficient diet results in a decreased D1R (dopamine receptor 1) and D2R (dopamine receptor 2) density in the caudate/putamen [28] but there may be a dose effect [29] and a timing effect [30]. In addition some of the effects can be reversed by replenishing iron in the diet [28]. Other models of post-weaning iron deficiency demonstrate decreased DAT density in rat caudate/putamen in males but not in females [22], [29]. The neurochemical alterations due to iron deficiency also manifest in motor abnormalities, as gestationally iron-deficient pups nursing from iron-deficient dams exhibited locomotor impairment at post-natal day 21 [24].

In summary, there are numerous models of gestational and/or neonatal iron deficiency and the impact on the dopaminergic system varies with the severity and developmental timing of iron deficiency. Collectively, these models demonstrate that the dopaminergic system is highly sensitive to iron levels. Although adequate iron intake is critical for normal growth and development, the data suggest that there is a window of opportunity early in development when iron levels can be normalized in iron-deficient offspring and the long-lasting effects of iron development can be minimized or even avoided [23]. This is clearly an important area for additional basic research with animal models and underscores the need for clinical studies because of the prevalence of iron deficiency in the world (see chapter by Beard in this issue).

Section snippets

Why is the nigra enriched in iron?

As discussed previously, many lines of evidence support the prevalence of high iron in the nigra, although the reason for high iron concentration has yet to be elucidated. It has been demonstrated that iron levels and deposition increase with age [14]. The mechanism of iron uptake into the brain reportedly involves transferrin [31] although recently ferritin uptake has also been demonstrated [32].

The expression of the transferrin receptor is regulated by intracellular levels of iron, so that in

Iron sequestration proteins

The primary mechanism for sequestering iron intracellularly is the protein ferritin. Ferritin consists of two distinct subunits, the heavy and light chains, which have no redundancy of function [44] and occur in varying ratios to achieve the mature 24-mer molecule. Light-chain ferritin (L-ferritin) is required for the long-term storage of iron [45], while heavy-chain ferritin (H-ferritin) has ferroxidase activity [46].

Cytosolic ferritins are controlled by iron levels of the cell — when iron is

Restless legs syndrome

Restless legs syndrome (RLS) is a neurological disorder reported to affect ∼ 8–10% of the population. Those who suffer from RLS describe their symptoms as uncontrollable urges to move the limbs, especially the legs (for a review of RLS, see [65], [66]). There are two generalized categories of RLS patients, those with early-onset (symptoms began before age 45) and late-onset (symptoms past age 45). Age of onset is particularly important in trying to study the disease, as early-onset patients show

Neurotoxin models

The use of neurotoxins to induce selective brain damage is a widely accepted method of experimental treatment, especially for Parkinson's disease (see [116] for a review). A common method of inducing nigrostriatal damage involves use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropridine). Although MPTP alone causes nigral cell death, the effect of MPTP increases with iron availability and age [117], [118].

Although MPTP is still widely used, the animal models are moving away from this synthetic

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