Iron as catalyst for oxidative stress in the pathogenesis of Parkinson's disease?

The mechanisms leading to degeneration of melanized dopaminergic neurons in the brain stem, and particularly in the substantia nigra zona compacta (SN ZC) in patients with Parkinson's disease (PD) are still unknown. Demonstrat ion of increased iron Fe(III) in SNZC of PD brain has suggested that Fe-mel anin interaction may contribute to oxidative neuronal damage. Energy disper sive X-ray electron microscopic analysis of the cellular distribution of tr ace elements revealed significant Fe-peaks, similar to those of a synthetic melanin-Fe(III) complex in intracytoplasmic electron-dense neuromelanin gr anules of SNZC neurons, with highest levels in a case of PD and Alzheimer's disease (AD). No Fe increase was found in Lewy bodies or in SN neurons of control specimens. The relevance of chemical reactions of dopamine (DA), 5- hydroxydopamine (5-OHDA), and 6-hydroxydopamine (6-OHDA) with Fe(III) and w ith dioxygen for the pathogenesis of PD was investigated. An initiating mec hanism related to interaction between Fe and neuromelanin is suggested whic h results in accumulation of Fe(III) and a continuous production of cytotox ic species inducing a cascade of pathogenic reactions ultimately leading to neuronal death.