Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson's disease

Abstract

Neuromelanin (NM) is a granular, dark brown pigment produced in some but not all of the dopaminergic neurons of the human substantia nigra (SN). In Parkinson's disease (PD) the pigmented dopaminergic neurons of the SN degenerate, suggesting that this process is related to the presence of NM. As yet it is unknown whether NM in the parkinsonian brain differs from that found in healthy tissue and thus may fulfil a different role within this tissue. The function of NM within the pigmented neurons is unknown but other melanins are believed to play a protective role via attenuation of free radical damage. Experimental evidence suggests that NM may also exhibit this characteristic, possibly by direct inactivation of free radical species or via its ability to chelate transition metals, such as iron. NM has the ability to bind a variety of metals, seven per cent of isolated NM is reported to consist of Fe, Cu, Zn and Cr. Iron is of particular interest as this metal is highly concentrated within the SN. Up to 20 per cent of the total iron contained in the SN from normal subjects is bound within NM. Further, it was demonstrated that NM contains a protein component and that iron is bound to NM in the ferric form. Increased tissue iron found in the parkinsonian SN may saturate iron-chelating sites on NM, and a looser association between iron and NM may result in an increased, rather than decreased, production of free radical species. It is hypothesized that this redox-active iron could be released and involved in a Fenton-like reaction leading to an increased production of oxidative radicals. The resultant radical-mediated cytotoxicity may contribute to cellular damage observed in PD.

Investigations of differences in iron oxidation state inside single neurons from substantia nigra of Parkinson’s disease and control patients using the micro-XANES technique

“…NM has a strong binding capacity, especially for Fe [22]. For normal subjects up to 20% of SN Fe is bound to NM (in the ferric form) [23]. The function of NM within the pigmented neurons is not fully known; however, according to the existing evidence it can play some protective role against free-radical damage either by direct inactivation of free-radical species or via its ability to chelate transition metals [23].…”

“…For normal subjects up to 20% of SN Fe is bound to NM (in the ferric form) [23]. The function of NM within the pigmented neurons is not fully known; however, according to the existing evidence it can play some protective role against free-radical damage either by direct inactivation of free-radical species or via its ability to chelate transition metals [23]. Gerlach et al [23] suggested that an increased Fe level in PD SN may saturate Fe-chelating sites on NM and cause a looser association between Fe and NM.…”

“…The function of NM within the pigmented neurons is not fully known; however, according to the existing evidence it can play some protective role against free-radical damage either by direct inactivation of free-radical species or via its ability to chelate transition metals [23]. Gerlach et al [23] suggested that an increased Fe level in PD SN may saturate Fe-chelating sites on NM and cause a looser association between Fe and NM. As a result, redox-active Fe could be released and involved in a Fenton-like reaction leading to an increased production of oxidative radicals.…”

Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood–CSF barrier in vitro

“…Abnormal metabolism of iron in the systemic circulation and in the central nervous system (CNS) is reportedly associated with the etiology of a number of neurodegenerative diseases (Berg et al, 2001;Double et al, 2000;Gerlach et al, 2003). Cellular iron overload in the basal ganglia, particularly in the substantia nigra, may catalyze the generation of reactive oxygen species and enhance lipid peroxidation.…”

Role of tea catechins in prevention of aging and age-related disorders

“…It has been reported that oxidative stress is involved as one of the causes in neurodegenerative disorders like AD and PKD (Gotz et al, 1990;Riederer et al, 1989;Perry et al, 2002) and age associated behaviour deficits (Shukitt-Hale, 1999). Apart from oxidative stress, inflammatory changes and iron accumulation (Gerlach et al, 2003;Youdim et al, 2004) have been suggested and reported to be involved in neurodegenerative diseases. Iron accumulation occurs in specific areas of the brain where degeneration occurs, in both PKD and AD (Riederer et al, 1989).…”