The roles of neuromelanin, binding of metal ions, and oxidative cytotoxicity in the pathogenesis of Parkinson's disease: A hypothesis

摘要: A characteristic feature of both Parkinson's disease (idiopathic paralysis agitans) and normal aging is loss pigmented neurons in the substantia nigra. This has been found to correlate with accumulation neuromelanin oxidative stress this brain region, but a clear association between these factors not established. Based on our recent demonstration that true melanin, containing bound metal ions situ, we present general model for its vivo hypotheses (1) it cytoprotective function sequestration redox-active under conditions (2) cytotoxic role pathogenesis disease. Thus, accumulates normally through autooxidation catecholamines serves tightly bind ions, processes which would accelerate intracellular or extracellular stress. known properties however, also potential exacerbating stress, eg by generating H2O2 when intact releasing if loses integrity; reactions modulate reactivity neuromelanin. By overwhelming antioxidative defense mechanisms, such positive-feedback cycle could turn condition chronic repeated vulnerable into an acute crisis, leading cellular death. If cumulative duration and/or degree severe enough, neuronal depletion be sufficient cause during life. One possible trigger cascade suggested increased nigral iron contents postmortem parkinsonian brains correlation urban living where exposure heavy high: saturation ions. therefore may form accelerated nigra associated environmental toxins central, active role.