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.

Coordination Mechanism in Dopamine Neurons of the <em>Substantia Nigra Pars Compacta</em> and Norepinephrine Neurons of the <em>Locus Coeruleus</em>

“…(Mostert et al, 2012). These observations are consistent with the pi-conjugated structure of melanin, because conjugated polymers can have conductive or semiconductive properties (Haining and Achat-Mendes, 2017;Ito, 2006). In addition, one documented function of neuromelanin is its ability to attract ferritin, as ferritin has been demonstrated to be present in proximity to the neuromelanin of the SNc (Tribl et al, 2009).…”

“…Some observers have suggested that it is detritus that accumulates with age (Haining and Achat-Mendes, 2017). Others have suggested that it might function to collect heavy metals and other material that might otherwise damage the neuron (Zecca et al, 2008).…”

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

“…Functionally, NM is believed to bind, store, protect, and release free dopamine, regulate redox‐active iron to minimize pro‐oxidant Fenton chemistry, and sequester a range of potentially toxic metal cations (zinc, copper, manganese, chromium, cobalt, mercury, lead, and cadmium) and chemicals (derivatives of paraquat, salsolinol, MPTP; Haining & Achat‐Mendes, ). Neuromelanin therefore bears closer resemblance to a protective cellular scaffold, rather than merely an aggregate of metabolic products, which is capable of sequestering toxic chemicals away from cellular compartments where they can participate in damaging biochemical reactions.…”

Automatic substantia nigra segmentation in neuromelanin-sensitive MRI by deep neural network in patients with prodromal and manifest synucleinopathy

“…The death of these neurons leads to the depletion of dopamine in the corpus striatum ultimately causing parkinsonian symptoms, i.e. akinesia, tremor, and rigidity that are typical for Parkinson's disease (PD) (Zecca et al 2001, Haining andAchat-Mendes 2017). Since there is a functional reserve in the number of dopaminergic neurons, parkinsonism appears only when approximately 50 % of neurons are lost.…”