The role of transition metals in the pathogenesis of Parkinson's disease.
The mechanisms that lead to degeneration of melanized dopaminergic neurons in the brain stem, and particularly in the substantia nigra (SN) in patients with Parkinson's disease (PD) are still unknown. Demonstration of increased iron (Fe) in SN of PD brain has suggested that Fe-melanin interaction may contribute to oxidative neuronal damage. Energy dispersive X-ray electron microscopic analysis of the cellular distribution of trace elements revealed significant Fe peaks, similar to those 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 in 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 for 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 promote the formation of cytotoxic hydroxyl free radicals (.OH) which, in turn, initiate lipid peroxidation and consequent cell damage. While in vitro studies indicate that DA oxidation leading to melanin formation is independent of metal ions, saturation of melanin with large amounts of Fe3+ causes a significant generation of free .OH radicals. The relevance of the events induced by the melanin-Fe complex for the degeneration of dopaminergic neurons in PD is discussed. Free redox-active metal ions in the cytoplasm may cause site-specific peroxidation and thus exert neurotoxic effects. Excessive hydrogen peroxide in post mortem frontal cortex of a patient with PD and AD could be shown by confocal fluorescence microscopy, and this observation may be a direct indicator of oxidative stress.
Kienzl
E
E
Ludwig Boltzmann Institute of Clinical Neurobiology, Lainz Hospital, Vienna, Austria.
Puchinger
L
L
Jellinger
K
K
Linert
W
W
Stachelberger
H
H
Jameson
R F
RF
D018663:Adrenergic Agents / Q000378:metabolism; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D004577:Electron Probe Microanalysis; D006801:Humans; D006892:Hydroxydopamines / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008670:Metals / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D016627:Oxidopamine / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D013378:Substantia Nigra / Q000378:metabolism
D018663:Adrenergic Agents; D006892:Hydroxydopamines; D008670:Metals; C027802:5-hydroxydopamine; D016627:Oxidopamine; D007501:Iron; D004298:Dopamine