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

Abstract

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

The Effects of Nitric Oxide on the Oxidations ofl-Dopa and Dopamine Mediated by Tyrosinase and Peroxidase

“…1). The formation and possible role of neuromelanin in the etiology of Parkinson's disease continue to be issues of considerable interest (56,59), because, as a redox-active polymer, the pigment has the capacity to engage in electron transfer processes. Depending on the prevailing intra-and extracellular environments, melanins can react with different reducing or oxidizing species and, thus, be either cytoprotective or cytotoxic (24,60).…”

Natural melanin pigments and their interfaces with metal ions and oxides: emerging concepts and technologies

“…[84] Neuromelanin has been reported to have a dichotomous role (adverse or protective): beneficial when it reduces the oxidative stress in the brain due to its ability to bind cations; detrimental when it exacerbates the oxidative stress releasing H 2 O 2 or by reducing redox-active metals to a more reactive state. [85][86][87] Particular efforts have been made in understanding the binding of iron to neuromelanin, [76,[88][89][90][91][92][93][94][95] as iron was reported in dopaminergic neurons of Parkinsonian brains. [8] Recently, Sepia melanin has been identified as a suitable model to describe the binding characteristics of neuromelanin.…”

The surface oxidation potential of human neuromelanin reveals a spherical architecture with a pheomelanin core and a eumelanin surface

“…With the onset and progression of PD, the concentration of NM decreases rapidly as pigmented dopaminergic neurons are selectively degraded while nonpigmented neurons are mostly spared (6). A direct, causal link between NM concentration and neuronal vulnerability has not yet been demonstrated, although several hypotheses exist (7)(8)(9). In the regions of highest neuronal loss, namely the SN, studies have shown an increase in iron levels in the late stages of PD (10).…”