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

Abstract

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.

Keywords: Parkinson's disease; dopamine; dopamine storage; neurodegeneration; neuromelanin; neurotoxicity.

Figure 1

Hypothetical role of Neuromelanin (NM) in the storage and release of dopamine. A dopaminergic axon terminal is shown, with dopamine (DA) being synthesized and packed into vesicles via vesicular monoamine transporters (VMAT) for release into the synapse. Released dopamine is taken up through a dopamine transporter (DAT). Excess cytosolic dopamine is thought to co-polymerize with cysteine into a polymer of ill-defined composition which is eventually packaged into a larger double-membrane bound vesicle (NM granule). It is known that this pigmented granule sequesters toxins such as methyl phenyl pyridinium ion. We hypothesize that molecular sequestration is in fact the natural role of this pigmented granule, and that dopamine is the intended beneficiary of this uniquely reducing environment. Should a mechanism be discovered (question mark) whereby sequestered dopamine could be re-released upon specific triggering, this seems to provide a complete self-reinforcing molecular memory loop. Although such a re-release mechanism is purely speculative at this time, a number of interesting plausible scenarios are apparent, including optical and electrical stimulation of the granule, changes in cellular pH or oxidation state, or displacement of NM-bound dopamine by alternate catecholamines or metal ions. We suggest that interruption of this putative sequestration and release mechanism may underlie the molecular basis of Parkinson's disease initiation.