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 microg/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.

Fig. 1.

Transmission electron microscopic images of pigmented organelles. (A–D) In putamen (A), premotor cortex (B), cerebellum (C), and substantia nigra (D) of the human brain, intraneuronal organelles containing dark pigment (arrow) and lipid droplets (arrowhead) are observed. (Scale bars, 1 μm.) (E and F) In aggregates of pigmented organelles isolated from cerebellum (E) and from substantia nigra (F), the same morphology with dark pigment (arrow) and lipid droplets (arrowhead) is present. [Scale bars, 1 μm (E) and 0.5 μm (F).]

Fig. 2.

Microscopic studies of isolated pigments. (A–D) Scanning electron microscopic images of pigment granules from different regions of the human brain: putamen (A), premotor cortex (B), cerebellum (C), and substantia nigra (D). (Scale bars, 200 nm.) (E) Atomic force microscopic image (phase) of pigment isolated from premotor cortex. (Scale bar, 100 nm.) (F) Wavelength-dependent UV free electron laser photoelectron emission microscopic data plotted for pigments isolated from different regions of the human brain, establishing that all have a common surface oxidation potential.

Fig. 3.

Concentration of metals in pigments from putamen (A), premotor cortex (B), cerebellum (C), and substantia nigra (D). Values are nanograms per milligram pigment (mean ± SEM; n ≥ 2), and relative ratios of accumulation are metal concentration in pigments per metal concentration in the brain region.