Neuromelanin, one of the most overlooked molecules in modern medicine, is not a spectator.

The loss of pigmented neurons from the human brain has long been the hallmark of Parkinson's disease (PD). Neuromelanin (NM) in the pre-synaptic terminal of dopamine neurons is emerging as a primary player in the etiology of neurodegenerative disorders including PD. This mini-review discusses the interactions between neuromelanin and different molecules in the synaptic terminal and describes how these interactions might affect neurodegenerative disorders including PD. Neuromelanin can reversibly bind and interact with amine containing neurotoxins, e.g. , MPTP, to augment their actions in the terminal, eventually leading to the instability and degeneration of melanin-containing neurons due to oxidative stress and mitochondrial dysfunction. In particular, neuromelanin appears to confer susceptibility to chemical toxicity by providing a large sink of iron-bound, heme-like structures in a pi-conjugated system, a system seemingly purposed to allow for stabilizing interactions including pi-stacking as well as ligand binding to iron. Given the progressive accumulation of NM with age corresponding with an apparent decrease in dopamine synthetic pathways, the immediate question of whether NM is also capable of binding dopamine, the primary functional monoamine utilized in this cell, should be raised. Despite the rather glaring implications of this finding, this idea appears not to have been adequately addressed. As such, we postulate on potential mechanisms by which dopamine might dissociate from neuromelanin and the implications of such a reversible relationship. Intriguingly, if neuromelanin is able to sequester and release dopamine in membrane bound vesicles, this intracellular pre-synaptic mechanism could be the basis for a form of chemical memory in dopamine neurons.