Riddles in the dark: Decoding the relationship between neuromelanin and neurodegeneration in locus coeruleus neurons

Abstract

The noradrenergic locus coeruleus (LC) is among the first regions of the brain affected by pathology in both Alzheimer's disease (AD) and Parkinson's disease (PD), but the reasons for this selective vulnerability are not completely understood. Several features of LC neurons have been proposed as contributing factors to this dysfunction and degeneration, and this review will focus on the presence of neuromelanin (NM). NM is a dark pigment unique to catecholaminergic cells that is formed of norepinephrine (NE) and dopamine (DA) metabolites, heavy metals, protein aggregates, and oxidated lipids. We cover what is currently known about NM and the limitations of historical approaches, then discuss the new human tyrosinase (hTyr) model of NM production in rodent catecholamine cells in vivo that offers unique opportunities for studying its neurobiology, neurotoxicity, and potential of NM-based therapeutics for treating neurodegenerative disease.

Keywords: Alzheimer’s disease; Dopamine; Locus coeruleus; Neuromelanin; Norepinephrine; Parkinson’s disease; Tyrosinase.

Figure 1.. Biosynthesis of Neuromelanin in Locus Coeruleus Neurons

Neuromelanin (NM) is formed as a byproduct of the catecholamine synthesis and metabolism pathway. This pathway begins with the conversation of tyrosine to L-DOPA, which is then synthesized further to form the neurotransmitter dopamine (DA). In the presence of iron (Fe³⁺) or copper (Cu²⁺), DA and NE can form quinones, which are toxic to neurons. The auto-oxidation of dopaquinones is believed to contribute directly to the formation of pigment in catecholamine neurons. DA is trafficked into synaptic vesicles by the vesicular monoamine transporter (VMAT), where it is converted to norepinephrine (NE) by the enzyme dopamine β-hydroxylase (DBH). Following vesicular fusion and release upon neuron stimulation, extracellular NE is taken up by the NE transporter (NET) and either repackaged into synaptic vesicles, oxidized by Fe³⁺ or Cu²⁺ to form quinones, or converted into the metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) by the mitochondrial enzyme monoamine oxidase A (MAO-A). DOPEGAL is eventually converted to the metabolite 3-Methoxy-4-hydroxyphenylglycol MHPG by catechol-O-methyltransferase (COMT). These heavy metal, pigment, and metabolite byproducts bind with protein aggregates in the cell and are collected for degradation by autophagosomes. If the components cannot be degraded fully, the phagosome encloses the components into a membrane, forming the final NM granule.

Figure 2:. Properties of Neuromelanin Over Time.

Neuromelanin (NM) accumulates over time with normal aging but its concentration declines as neurons die in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. NM binds heavy metals and toxic catechols in the cytosol, initially serving as a neuroprotective mechanism within the cell. However, NM can become toxic by overwhelming intracellular machinery and/or by harming surrounding cells following release by dying neurons.