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New Melanic Pigments in the Human Brain That Accumulate in Aging and Block Environmental Toxic Metals

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New Melanic Pigments in the Human Brain That Accumulate in Aging and Block Environmental Toxic Metals New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals Luigi Zeccaa,1, Chiara Belleia, Patrizia Costia, Alberto Albertinia, Enrico Monzanib, Luigi Casellab, Mario Gallorinic, Luigi Bergamaschic, Alberto Moscatellid, Nicholas J. Turrod,2, Melvin Eisnere, Pier Raimondo Crippaf, Shosuke Itog, Kazumasa Wakamatsug, William D. Bushh, Weslyn C. Wardh, John D. Simonh, and Fabio A. Zuccaa aInstitute of Biomedical Technologies, Italian National Research Council, 20090 Segrate, Milan, Italy; bDepartment of General Chemistry, University of Pavia, 27100 Pavia, Italy; cNational Institute of Metrology, Unit of Radiochemistry and Spectroscopy, 27100 Pavia, Italy; dDepartment of Chemistry, Columbia University, New York, NY 10027; eDepartment of Physics, University of Houston, Houston, TX 77204-5506; fDepartment of Environmental Sciences, University of Parma, 43100 Parma, Italy; gDepartment of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan; and hDepartment of Chemistry, Duke University, Durham, NC 27708 Contributed by Nicholas J. Turro, September 9, 2008 (sent for review August 7, 2008) Neuronal pigments of melanic type were identified in the putamen, Neuromelanin in the substantial nigra and locus coeruleus is an cortex, cerebellum, and other major regions of human brain. These electron-dense brown/black pigment composed of aggregates of pigments consist of granules 30 nm in size, contained in organelles Ϸ30-nm diameter spheres with a pheomelanin core and eumelanin together with lipid droplets, and they accumulate in aging, reaching surface and a pheomelanin/eumelanin ratio of 3:1 (12, 13). Eu- concentrations as high as 1.5–2.6 ␮g/mg tissue in major brain regions. melanin is characterized by dihydroxyindole groups formed by DA These pigments, which we term neuromelanins, contain melanic, oxidation and is responsible for the metal-chelating ability of lipid, and peptide components. The melanic component is aromatic in neuromelanin (14). Pheomelanin is generated by oxidation of structure, contains a stable free radical, and is synthesized from the cysteinyl-dopamine (Cys-DA) and contains benzothiazine groups. precursor molecule cysteinyl-3,4-dihydroxyphenylalanine. This con- In addition to the mentioned melanic component of neuromelanin, trasts with neuromelanin of the substantia nigra, where the melanic there are also poorly-characterized peptide and aliphatic compo- precursor is cysteinyl-dopamine. These neuronal pigments have some nents (15). structural similarities to the melanin found in skin. The precursors of Before this work, it was not known whether pigments with lipid components of the neuromelanins are the polyunsaturated lipids structure and function similar to neuromelanin are present in present in the surrounding organelles. The synthesis of neuromela- noncatecholaminergic neurons and in brain regions other than the nins in the various regions of the human brain is an important substantia nigra and locus coeruleus. In this work, we establish the protective process because the melanic component is generated presence of a type of aging pigment in neurons of the putamen, through the removal of reactive/toxic quinones that would otherwise premotor cortex, and cerebellum and compare them with the cause neurotoxicity. Furthermore, the resulting melanic component neuromelanin of the substantia nigra. We have also examined their serves an additional protective role through its ability to chelate and structure, behavior in aging, and interaction with metal ions and accumulate metals, including environmentally toxic metals such as lipids. mercury and lead. Results lipids ͉ neuromelanin ͉ brain aging ͉ neurodegenerative An Electron-Dense Pigment Is Contained in Organelles in the Neurons of the Putamen, Premotor Cortex, Cerebellum, and Substantia Nigra of the Human Brain. Transmission electron microscopy was used to euromelanins occur as dark brown granules with variable investigate the existence of organelles containing melanic pigments distribution in catecholamine neurons of the substantia nigra N in neurons of the putamen, premotor cortex, and cerebellum. Slices and locus coeruleus in the brains of humans and different animal of these regions from human brains aged 70–80 years showed species (1). In the human brain, neuromelanin has been found, pigmented organelles similar to those in the substantia nigra (Fig. isolated, and characterized only in the dopamine (DA) neurons 1 A–D). Each organelle exhibited a typical double membrane, a contained in the substantia nigra and in the norepinephrine neu- large amount of dark pigment, lipid deposits, and a protein matrix. rons in the locus coeruleus, and these two neuromelanins share The ratios of these components varied with the brain region. some common structural features (2). In both of these regions of the Organelle shape also varied from round to oblong, with sizes human brain, the neuromelanin concentration normally increases ranging from 0.5 to 3.0 ␮m. The number of neurons containing linearly with age. In Parkinson’s disease, the tissue concentration of organelles decreased in the order: substantia nigra Ͼ putamen Х neuromelanin decreases dramatically because DA pigmented neu- premotor cortex Ͼ cerebellum. To characterize these organelles rons are preferentially lost compared with nonpigmented ones (3, 4). Reduced neuronal content of neuromelanin in substantia nigra has been reported in patients with Parkinson’s disease (3), Alzhei- Author contributions: L.Z., A.A., L.C., N.J.T., S.I., and J.D.S. designed research; L.Z., C.B., P.C., mer’s disease (5), and Rett syndrome (6). In neuronal cultures and E.M., L.C., M.G., A.M., M.E., P.R.C., K.W., W.C.W., and F.A.Z. performed research; L.B., A.M., in the human brain, neuromelanin synthesis is driven by excess K.W., W.D.B., and W.C.W. contributed new reagents/analytic tools; L.Z., P.C., A.A., L.C., M.G., N.J.T., M.E., P.R.C., S.I., W.C.W., J.D.S., and F.A.Z. analyzed data; and L.Z., A.A., L.C., cytosolic catechols not accumulated in synaptic vesicles, is inversely N.J.T., M.E., S.I., J.D.S., and F.A.Z. wrote the paper. related to the expression of vesicular monoamine transporter 2, and The authors declare no conflict of interest. is directly related to the vulnerability of neurons during aging. It has 1To whom correspondence may be addressed at: Institute of Biomedical Technologies, Italian been suggested that neuromelanin synthesis protects the neurons in National Research Council, Via Cervi, 93, 20090 Segrate, Italy. E-mail: [email protected]. the substantia nigra because it removes neurotoxic quinones (7, 8). 2To whom correspondence may be addressed. E-mail: [email protected]. Furthermore, the neuromelanin in the substantia nigra can trap This article contains supporting information online at www.pnas.org/cgi/content/full/ endogenous and environmental toxins and immobilize them as 0808768105/DCSupplemental. NEUROSCIENCE stable adducts, thus protecting against toxicity (9–11). © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0808768105 PNAS ͉ November 11, 2008 ͉ vol. 105 ͉ no. 45 ͉ 17567–17572 Downloaded by guest on September 28, 2021 A B A B C D C D E F E 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 Fig. 1. Transmission electron microscopic images of pigmented organelles. isolated from premotor cortex. (Scale bar, 100 nm.) (F) Wavelength-dependent (A–D) In putamen (A), premotor cortex (B), cerebellum (C), and substantia nigra UV free electron laser photoelectron emission microscopic data plotted for pig- (D) of the human brain, intraneuronal organelles containing dark pigment ments isolated from different regions of the human brain, establishing that all (arrow) and lipid droplets (arrowhead) are observed. (Scale bars, 1 ␮m.) (E and F) have a common surface oxidation potential. 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 ␮m(E) and 0.5 ␮m(F).] nm and could be assigned to the quinone residues of the melanic/ peptidic component of the pigments. and their contents, they were isolated by a multistep gradient Isolation of the Pigments from Human Brain Regions for Structural centrifugation and visualized by electron microscopy (Fig. 1 E and Investigations. The pigments from organelles of the same brain F). The morphology of the isolated organelles confirms the pres- regions were isolated and purified in amounts sufficient for accurate ence of both dark pigment and lipid droplets. structural determinations and for comparison with neuromelanin from substantia nigra (2, 15). For isolation of the pigments, tissues from brain areas were washed with phosphate buffer and SDS and UV-Visible Spectra Confirm the Presence of Melanic Pigments in the successively treated with proteinase to remove proteins and meth- Neuronal Organelles of Different Regions of the Human Brain. To anol/hexane to remove lipids. The dark brown pigments are spar- assess the presence of melanic components in the dark pigment of ingly soluble in alkaline solution and polar organic solvents. organelles prepared from the putamen, premotor
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