Iron‐Melanin Complex in Substantia Nigra of Parkinsonian Brains: An X‐Ray Microanalysis

Abstract

Using energy-dispersive x-ray analysis on an electron microscope working in the scanning transmission electron microscopy mode equipped with a microanalysis system, we studied the subcellular distribution of trace elements in neuromelanin-containing neurons of the substantia nigra zona compacta (SNZC) of three cases of idiopathic Parkinson's disease (PD) [one with Alzheimer's disease (AD)] and of three controls, in Lewy bodies of SNZC, and in synthetic dopamine-melanin chemically charged or uncharged with Fe. Weak but significant Fe peaks similar to those of a synthetic melanin-Fe3+ complex were seen only in intraneuronal highly electron-dense neuromelanin granules of SNZC cells of PD brains, with the highest levels in a case of PD plus AD, whereas a synthetic melanin-Fe2+ complex showed much lower iron peaks, indicating that neuromelanin has higher affinity for Fe3+ than for Fe2+. No detectable Fe was seen in nonmelanized cytoplasm of SNZC neurons and in the adjacent neuropil in both PD and controls, in Lewy bodies in SNZC neurons in PD, and in synthetic dopamine-melanin uncharged with iron. These findings, demonstrating for the first time a neuromelanin-iron complex in dopaminergic SNZC neurons in PD, support the assumption that an iron-melanin interaction contributes significantly to dopaminergic neurodegeneration in PD and PD plus AD.

Progressive Degeneration of Human Mesencephalic Neuron-Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway

“…In the SN of PD patients, redox-active iron levels are increased by 30 -35% compared with age-matched controls (for review, see Zecca et al, 2004;Götz et al, 2004). Neuromelanin, a dark pigment produced in catecholaminergic neurons of the human SN and locus ceruleus, acts as a storage system for iron in dopaminergic neurons (Zecca et al, 2002) and has been found to associate with large amounts of iron in diseased nigral tissue (Jellinger et al, 1992(Jellinger et al, , 1993. Neuromelanin could potentially serve a neuroprotective function by sequestering free intracellular iron.…”

Natural melanin pigments and their interfaces with metal ions and oxides: emerging concepts and technologies

“…[84] Neuromelanin has been reported to have a dichotomous role (adverse or protective): beneficial when it reduces the oxidative stress in the brain due to its ability to bind cations; detrimental when it exacerbates the oxidative stress releasing H 2 O 2 or by reducing redox-active metals to a more reactive state. [85][86][87] Particular efforts have been made in understanding the binding of iron to neuromelanin, [76,[88][89][90][91][92][93][94][95] as iron was reported in dopaminergic neurons of Parkinsonian brains. [8] Recently, Sepia melanin has been identified as a suitable model to describe the binding characteristics of neuromelanin.…”

Original article Association of monoamine oxidase B and catechol-O-methyltransferase polymorphisms with sporadic Parkinson’s disease in an Iranian population

“…In the individuals with the L allele, the COMT protein is thermolabile. Decreased COMT activity may result in increased metabolism of dopamine to neuromelanin that can enhance the formation of cytotoxic radicals contributing to neuronal degeneration [21]. As the A allele of COMT G1947A is associated with low COMT activity of soluble COMT [37], the A allele of COMT G1947A may be linked to an increased risk of PD.…”