Neuromelanin associated redox‐active iron is increased in the substantia nigra of patients with Parkinson's disease

Abstract

Degeneration of dopaminergic neurones during Parkinson's disease is most extensive in the subpopulation of melanizedneurones located in the substantia nigra pars compacta. Neuromelanin is a dark pigment produced in the dopaminergic neurones of the human substantia nigra and has the ability to bind a variety of metal ions, especially iron. Post-mortem analyses of the human brain have established that oxidative stress and iron content are enhanced in association with neuronal death. As redox-active iron (free Fe 2+ form) and other transition metals have the ability to generate highly reactive hydroxyl radicals by a catalytic process, we investigated the redox activity of neuromelanin (NM)-aggregates in a group of parkinsonian patients, who presented a statistically significant reduction () 70%) in the number of melanizedneurones and an increased non-heme (Fe 3+) iron content as compared with a group of matched-control subjects. The level of redox activity detected in neuromelanin-aggregates was significantly increased (+ 69%) in parkinsonian patients and was highest in patients with the most severe neuronal loss. This change was not observed in tissue in the immediate vicinity of melanized-neurones. A possible consequence of an overloading of neuromelanin with redox-active elements is an increased contribution to oxidative stress and intraneuronal damage in patients with Parkinson's disease.

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

“…As a result, redox-active Fe could be released and involved in a Fenton-like reaction leading to an increased production of oxidative radicals. The results of Faucheux et al [24] showed that the redox activity of NM aggregates in a group of parkinsonian patients increased significantly (by 69%) and was highest in patients with the most severe neuronal loss. Such an overloading of NM with redox-active elements may contribute to oxidative stress and intraneuronal damage in patients with PD [24].…”

“…The results of Faucheux et al [24] showed that the redox activity of NM aggregates in a group of parkinsonian patients increased significantly (by 69%) and was highest in patients with the most severe neuronal loss. Such an overloading of NM with redox-active elements may contribute to oxidative stress and intraneuronal damage in patients with PD [24]. On the other hand, it is necessary to mention that extraneuronal NM from dying neurons is phagocytosed by microglia and is associated with its activation.…”

Transition metal distribution in the brain and spinal cord of a dysmyelinated rodent model

“…Disruptions to transition metal concentration homeostasis (such as Mn, Fe, Cu and Zn) in the brain are implicated in neurodegenerative disorders such an Alzheimer's, Parkinson's and Multiple Sclerosis [25][26][27][28] where a common symptom of these diseases is demyelination -a loss of the protein/lipid complex myelin. The myelin sheath is an insulating protein and fatty layer that encapsulates the axons of neurons in the central and peripheral nervous system of vertebrates to improve conduction of electrical signals.…”

Oxidative Stress in Parkinson's Disease; Parallels Between Current Animal Models, Human Studies and Cells

“…Post-mortem analyses of the substantia nigra in PD patients have shown effects of oxidative stress with a decrease in glutathione (GSH) levels, increased levels of iron, neuromelanin associated redox-active iron, lipid peroxidation, protein oxidation and DNA damage (Jenner and Olanow 1998, Faucheux et al 2003, Dexter et al 1989). These changes may directly induce nigral cell degeneration via oxidative stress or render neurons susceptible to the actions of toxins.…”

“…The effects of oxidative stress are demonstrated in PD patients who have decreased GSH levels, increased levels of iron, neuromelanin associated redox-active iron, lipid peroxidation, protein oxidation and DNA damage in the substantia nigra (Jenner and Olanow 1998, Faucheux et al 2003, Dexter et al 1989. Antioxidant therapy has been suggested to ameliorate these effects.…”