Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. Neuromelanin is expressed in large quantities by the dopaminergic cells of the substantia nigra, and is thought to contribute to the dark color of that structure.
Importance in humans
Neuromelanin is found in higher concentrations among humans than in other primates. There is also speculated to be a link between vulnerability of neuromelanin-containing neurons to cell death in Parkinson's Disease. It has also been observed in higher amounts among aging mammals in the substantia nigra. It also has a high chelating ability for iron and an affinity for compounds such as lipids, pesticides and MPP+, suggesting a neuroprotective role.
The synthetic pathway for neuromelanin was largely unknown until recently. The pathway has been shown to be very complex as compared to other neurogenesis pathways. It had previously been thought to have been derived from dopamine but recent studies have shined a brighter light upon this process. In the biosythesis of neuromelanin in humans L-DOPA, the precursor to dopamine, is taken up by an amino acid transporter across the plasma membrane of the cell. L-DOPA is synthesized inside the cell by the enzyme tyrosine hydroxylase (TH). From L-DOPA dopamine is synthesized by the use of aromatic acid decarboxylase (AADC). Synaptic vesicles and endosomes accumulate cytosolic, free-floating in the cytoplasm of the cell, dopamine via VMAT2, vesicular monoamine transporter 2. This cytosolic dopamine is then transported to the mitochondria where it is metabolized by the enzyme monoamine oxidase. Excess dopamine and DOPA molecules are oxidized by iron catalysis into quinones and semiquinones. These quinones then react with proteins, lipids and cysteine which are then phagocytosed into bilamellar autophagic vacuoles and are permanently stored as neuromelanin.
Parkinson's Disease is caused by cell death in the substantia nigra. This cell death may be partly due to oxidative stress. This oxidation may be relieved by neuromelanin. It has been shown that patients with Parkinson's Diseases had 50% the amount of neuromelanin in the substantia nigra as compared to similar patients of their same age but without Parkinson's. The death of neuromelanin containing neurons in the substantia nigra, pars compacta, and locus coeruleus have been linked to Parkinson's Disease and also have been visualized in vivo with Neuromelanin MRI. Neuromelanin has been shown to bind neurotoxic and toxic metals that could promote neurodegeneration. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles.
Physical properties and structure
Neuromelanin gives specific brain sections, such as the substantia nigra, distinct color. It is a type of melanin and similar to other forms of peripheral melanin. It is insoluble in organic compounds, and can be labeled by silver stains. It is called neuromelanin because of its function and the color change that appears in tissues containing it. It contains black/brown pigmented granules. Neuromelanin is found to accumulate during ageing and is found during the first 2–3 years of life. It is believed to protect neurons in the substantia nigra from iron induced oxidative stress. It is considered a true melanin due to its stable free radical structure and it avidly chelates metals.
Neuromelanin was first discovered in the 1930s, though it has been thought to serve no function until recently. It is now believed to play a vital role in preventing cell death in certain parts of the brain. It has been linked to Parkinson's Disease and because of this possible connection, neuromelanin has been heavily researched in the last decade.
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