Neuromelanin in Parkinson's Disease: from Fenton Reaction to Calcium Signaling

Neuromelanin is supposed to play a key role in the pathogenesis of Parkinson's disease. A common theory is the formation of reactive oxygen species through the Fenton reaction catalyzed by neuromelanin-bound iron ions and subsequent death of the dopaminergic cells in the substantia nigra. From a physicochemical point of view, this pathway is rather implausible: a highly reactive radical built within a powerful radical scavenger would more promptly be inactivated before it might diffuse within the cell to reach a target to exert its deleterious potential. This review of the literature provides evidence for an interaction of neuromelanin with the calcium signaling pathway in Parkinson's disease and expands the view of the pathophysiological contribution of neuromelanin towards a cytoprotective involvement of this macromolecule in the calcium signaling system. More probably than being directly involved in the production of reactive oxygen species, neuromelanin may act as a calcium reservoir and thus protect dopaminergic cells from cell death. A loss of neuromelanin, as observed in the substantia nigra of Parkinson patients, would lead to enhanced calcium messaging through the loss of an important calcium reservoir and thus finally via the formation of reactive oxygen species to cell death within the substantia nigra.