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The neuromelanin pigment of the substantia nigra of the human brain is closely associated with lipids and other non-melanogenic compounds which appear to contribute to the unique and complex morphology of neuromelanin pigment granules. In this work we show that insoluble granules isolated from the human substantia nigra associate in vitro to form pigment aggregates similar to those present in the human brain. Extraction of neuromelanin-associated polar lipids by methanol and/or hexane significantly enhanced melanin aggregate size. A marked (10-fold) increase in granule size was seen after methanol treatment, whereas the application of hexane after methanol reduced this pro-aggregation effect. We have previously reported that hexane and methanol remove the neuromelanin-associated polyisoprenoids dolichol and cholesterol respectively. Thus, the current data suggests that pigment-associated lipids may be a factor regulating pigment aggregation and neuromelanin granule size in vivo.

Histopathological, biochemical and in vivo brain imaging techniques, such as magnetic resonance imaging and transcranial sonography, revealed a consistent increase of substantia nigra (SN) iron in Parkinson's disease (PD). Increased iron deposits in the SN may have genetic and non-genetic causes. There are several rare movement disorders associated with neurodegeneration, and genetic abnormalities in iron regulation resulting in iron deposition in the brain. Non-genetic causes of increased SN iron may be the result of a disturbed or open blood-brain-barrier, local changes in the normal iron-regulatory systems, intraneuronal transportation of iron from iron-rich area into the SN and release of iron from intracellular iron storage molecules. Major iron stores are ferritin and haemosiderin in glial cells as well as neuromelanin in neurons. Age- and disease dependent overload of iron storage proteins may result in iron release upon reduction. Consequently, the low molecular weight chelatable iron complexes may trigger redox reactions leading to damage of biomolecules. Additionally, upon neurodegeneration there is strong microglial activation which can be another source of high iron concentrations in the brain.

The massive, early and relatively circumscribed death of the dopaminergic neurons of the substantia nigra in Parkinson's disease has not yet been adequately explained. The characteristic feature of this brain region is the presence of neuromelanin pigment within the vulnerable neurons. We suggest that neuromelanin in the Parkinson's disease brain differs to that in the normal brain. The interaction of neuromelanin with iron has been shown to differ in the parkinsonian brain in a manner consistent with an increase in oxidative stress. Further, we suggest an interaction between the lipoprotein alpha-synuclein and lipidated neuromelanin contributes to the aggregation of this protein and cell death in Parkinson's disease. The available data suggest that the melaninisation of the dopaminergic neurons of the substantia nigra is a critical factor to explain the vulnerability of this brain region to early and massive degeneration in Parkinson's disease.

Despite physiological systems designed to achieve iron homeostasis, increased concentrations of brain iron have been demonstrated in a range of neurodegenerative diseases. These including the parkinsonian syndromes, the trinucleotide repeat disorders and the dementia syndromes. The increased brain iron is confined to those brain regions most affected by the degeneration characteristic of the particular disorder and is suggested to stimulate cell damage via oxidative mechanisms. Changes in central iron homeostasis have been most closely investigated in PD, as this disorder is well characterised both clinically and pathologically. PD is associated with a significant increase in iron in the degenerating substantia nigra (SN) and is measureable in living PD patients and in post-mortem brain. This increase, however, occurs only in the advanced stages of the disease, suggesting that this phenonoma may be a secondary, rather than a primary initiating event, a hypothesis also supported by evidence from animal experiments. The source of the increased iron is unknown but a variety of changes in iron homeostasis have been identified in PD, both in the brain and in the periphery. The possibility that an increased amount of iron may be transported into the SN is supported by data demonstrating that one form of the iron-binding glycoprotein transferrin family, lactotransferrin, is increased in surviving neurons in the SN in the PD brain and that this change is associated with increased numbers of lactotransferrin receptors on neurons and microvessels in the parkinsonian SN. These changes could represent one mechanism by which iron might concentrate within the PD SN. Alternatively, the measured increased in iron might result from a redistribution of ferritin iron stores. Ferritin is located in glial cells while the degenerating neurons do not stain positive for ferritin. As free radicals are highly reactive, it is unlikely that glial-derived free radicals diffuse across the intracellular space in sufficent quantities to damage neuronal constituents. If intracellular iron release contributes to neuronal damage it seems more probable that an intraneuronal iron source is responsible for oxidant-mediated damage. Such a iron source is neuromelanin (NM), a dark-coloured pigment found in the dopaminergic neurons of the human SN. In the normal brain, NM has the ability to bind a variety of metals, including iron, and increased NM-bound iron is reported in the parkinsonian SN. The consequences of these phenomena for the cell have not yet been clarified. In the absence of significant quantities of iron NM can act as an antioxidant, in that it can interact with and inactivate free radicals. On the other hand, in the presence of iron NM appears to act as a proxidant, increasing the rate of free radical production and thus the oxidative load within the vulnerable neurons. Given that increased iron is only apparent in the advanced stages of the disease it is unlikely that NM is of importance for the primary aetiology of PD. A localised increase in tissue iron and its interaction with NM may be, however, important as a secondary mechanism by increasing the oxidative load on the cell, thereby driving neurodegeneration.