THE ROLE OF TRANSITION-METALS IN THE PATHOGENESIS OF PARKINSONS-DISEASE

The mechanisms that lead to degeneration of melanized dopaminergic neu rons in the brain stem, and particularly in the substantia nigra (SN) in patients with Parkinson's disease (PD) are still unknown, Demonstra tion of increased iron (Fe) in SN of PD brain has suggested that Fe-me lanin interaction may contribute to oxidative neuronal damage. Energy dispersive X-ray electron microscopic analysis of the cellular distrib ution of trace elements revealed significant Fe peaks, similar to thos e of a synthetic melanin-Fe3+ complex, in intraneuronal electron-dense neuromelanin granules of the SN zona compacta, with highest levels in a case of PD and Alzheimer's disease (AD). No Fe increase was found i n Lewy bodies or in SN neurons of control specimens. The relevance of the in vitro chemical reactions of dopamine (DA), 5-hydroxydopamine (5 -OHDA), and 6-hydroxydopamine (6-OHDA) with Fe3+ and with dioxygens fo r the pathogenesis of PD was investigated, An initiating mechanism for a chain reaction is suggested by which excessive Fe3+ arises. Melanin can act as an efficient antioxidant and in the presence of Fe can pro mote the formation of cytotoxic hydroxyl free radicals (. OH) which, i n turn, initiate lipid peroxidation and consequent cell damage. While in vitro studies indicate that DA oxidation leading to melanin formati on is independent of metal ions, saturation of melanin with large amou nts of Fe3+ causes a significant generation of free . OH radicals. The relevance of the events induced by the melanin-Fe complex for the deg eneration of dopaminergic neurons in PD is discussed. Free redox-activ e metal ions in the cytoplasm may cause site-specific peroxidation and thus exert neurotoxic effects. Excessive hydrogen peroxide in post mo rtem frontal cortex of a patient with PD and AD could be shown by conf ocal fluorescence microscopy, and this observation may be a direct ind icator of oxidative stress.