New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals

Abstract

Neuronal pigments of melanic type were identified in the putamen, cortex, cerebellum, and other major regions of human brain. These pigments consist of granules 30 nm in size, contained in organelles together with lipid droplets, and they accumulate in aging, reaching concentrations as high as 1.5-2.6 g/mg tissue in major brain regions. These pigments, which we term neuromelanins, contain melanic, lipid, and peptide components. The melanic component is aromatic in structure, contains a stable free radical, and is synthesized from the precursor molecule cysteinyl-3,4-dihydroxyphenylalanine. This contrasts with neuromelanin of the substantia nigra, where the melanic precursor is cysteinyl-dopamine. These neuronal pigments have some structural similarities to the melanin found in skin. The precursors of lipid components of the neuromelanins are the polyunsaturated lipids present in the surrounding organelles. The synthesis of neuromelanins in the various regions of the human brain is an important protective process because the melanic component is generated through the removal of reactive/toxic quinones that would otherwise cause neurotoxicity. Furthermore, the resulting melanic component serves an additional protective role through its ability to chelate and accumulate metals, including environmentally toxic metals such as mercury and lead.lipids ͉ neuromelanin ͉ brain aging ͉ neurodegenerative

Biogenic Amines in Rett Syndrome: The Usual Suspects

“…Neuromelanin is purported to play a neuroprotective role in the substantia nigra, via its ability to chelate metal ions such as lead or mercury (Zecca et al 2008). It is possible that the reduced amount of neuromelanin pigment observed in RTT makes the dopaminergic neurons of the SNpc more vulnerable to stress and intracellular damage.…”

The Pigment in Alkaptonuria Relationship to Melanin and Other Coloured Substances: A Review of Metabolism, Composition and Chemical Analysis

“…The pigment is composed of aggregates of 30-nm diameter spheres with a pheomelanin core, a eumelanin surface and a pheomelanin-to-eumelanin ratio of 3:1 of indeterminate size. The complex has been shown to bind heavy metals (Zecca et al 2008). A recent study using proteomics of the melanin complex systems within neurones suggested the presence of endoplasmic reticulumderived chaperones, especially the transmembrane protein calnexin, located in lysosome-related melanosomes suggested to be a melanogenic chaperone (Tribl et al 2005).…”

Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis

“…Dopamine oxidation to o-quinones and their polymerization to neuromelanin seems to be a natural process because normal individuals have this pigment that increases with age in the substantia nigra [21]. The dopamine oxidation is catalyzed by metals such as manganese(III) that catalyzes this reaction both under anaerobic and aerobic conditions [22].…”

“…Neuromelanin is a dark pigment found in the substantia nigra and in the locus coeruleus of healthy individuals, which increases with age [21,64], suggesting that the formation of neuromelanin is not a neurotoxic reaction. Neuromelanin biosynthesis may begin with the autoxidation of catecholamines to o-quinones, followed by the addition of a thiol group, as observed in the brain [65,66].…”