Iron in Brain Development and Function

The brain has several characteristics that make it unique among organs with regard to iron metabolism. It resides behind a vascular barrier, which limits its access to plasma iron. A transport mechanism at the blood-brain barrier (BBB) moves iron across the endothelial cells and into the brain [25]. However, little is known about the mechanism of iron release into the brain or the regulation of the transport mechanism. The concentration of iron in various regions of the brain varies greatly. Regions of the brain that are associated with motor functions (extrapyramidal regions) tend to have more iron than non-motor-related regions [26] which might explain why movement disorders are commonly associated with iron imbalance. It is known that at birth these regions have little iron, however, with ageing they accumulate significant amount of iron, probably through axonal transport. The amounts of iron present is in excess of what is required by the various iron dependent processes (calculated to be about 5-10% of brain iron). The rest of the iron must have some other function.

In the brain, the most common cell type to stain for iron under normal conditions is the oligodendrocyte [27] which expresses both H- and L-ferritin. Neurons and microglia, have much lower amounts of ferritin present [27], neurons mostly

Isopeptide bond

Figure 8. The reactions involved in the attachment of ubiquitin to a protein. In the first part the carboxyl group of ubiquitin is coupled to Ej by a thioether linkage in a reaction driven by ATP hydrolysis. The activated ubiquitin is subsequently transferred to a sulfhydryl group of E2 and then in a reaction catalyzed by E3 to the e-amino group of a Lys residue on a condemned protein, thereby flagging the protein for proteolytic degradation by the 26S proteosome. (Reproduced with permission from [169]).

Isopeptide bond

Figure 8. The reactions involved in the attachment of ubiquitin to a protein. In the first part the carboxyl group of ubiquitin is coupled to Ej by a thioether linkage in a reaction driven by ATP hydrolysis. The activated ubiquitin is subsequently transferred to a sulfhydryl group of E2 and then in a reaction catalyzed by E3 to the e-amino group of a Lys residue on a condemned protein, thereby flagging the protein for proteolytic degradation by the 26S proteosome. (Reproduced with permission from [169]).

express H-ferritin while microglia appear to express L-ferritin [28,29]. Very little ferritin expression is seen in astrocytes. In the dopaminergic neurons of the substantia nigra and the noradrenergic neurons of the locus coeruleus, large amounts of iron are sequestered in neuromelanin granules [30].

Neuromelanin is synthesized by oxidation of excess cytosolic catechols that are not accumulated in synaptic vesicles by vesicular monoamine transporter-2 [31]. Neuromelanin binds iron avidly, forming stable octahedral complexes that contain high-spin oxyhydroxide iron(III) clusters [32]. Neuromelanin is a complex molecule whose structure is arranged as a multilayer system where each layer is a polymer composed of melanic groups bound to aliphatic and peptide chains. This melanic group contains benzothiazine and dihydroxyindole units (ratio 1:3) and the latter is responsible for the strong chelating ability for iron and other metals [31,33]).

The iron transport protein transferrin (Tf) was originally thought to be synthesized only by oligodendrocytes in the brain [34], although evidence for Tf mRNA has recently been found in neurons in the human substantia nigra [33]. Choroid plexus epithelial cells and other cells outside the brain that make Tf secrete transferrin, but it does not seem to be secreted by oligodendro-cytes [35]. There are two receptors in the brain for iron uptake - TFRs are expressed exclusively in the gray matter, whereas ferritin receptors are present only in white matter [36]. This dichotomous expression pattern is unique to the brain.

In summary, the brain is unique among organs because of the nonuniformity of iron distribution, both regionally and cellularly, and because of the apparent selectivity in cellular responsibilities for iron storage and mobilization, and presumably usage and methods of uptake.

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