The neuromelanin of human substantia nigra: structure, synthesis and molecular behaviour
The pigmented neurons of the substantia nigra (SN) are typically lost in Parkinson’s disease: however the possible relationship between neuronal vulnerability and the presence of neuromelanin (NM) has not been elucidated. Early histological studies reveal
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Summary. The pigmented neurons of the substantia nigra (SN) are typically lost in Parkinson's disease: however the possible relationship between neuronal vulnerability and the presence of neuromelanin (NM) has not been elucidated. Early histological studies revealed the presence of increasing amounts of NM in the SN with aging in higher mammals, showed that NM granules are surrounded by membrane, and comparatively evaluated the pigmentation of SN in different animal species. Histochemical studies showed the association of NM with lipofuscins. However, systematic investigations of NM structure, synthesis and molecular interactions have been undertaken only during the last decade. In these latter studies, NM was identified as a genuine melanin with a strong chelating ability for iron and affinity for compounds such as lipids, pesticides, and MPP+. The affinity of NM for a variety of inorganic and organic toxins is consistent with a postulated protective function for NM. Moreover, the neuronal accumulation of NM during aging, and the link between its synthesis and high cytosolic concentration of catechols suggests a protective role. However, its putative neuroprotective effects could be quenched in conditions of toxin overload.
Introduction Black-brown pigmented granules in the human central nervous system has been observed since the 1930's (Schrerer, 1939). The most pigmented regions are two mesencephalic areas, Sommering's substantia nigra (SN), and the locus coeruleus (LC) (Cotzias et aI., 1964; Graham, 1979; Zecca et aI., 1996). Histological studies displayed pigmentation in the SN of other mammals
R. Horowski et al. (eds.), Advances in Research on Neurodegeneration © Springer-Verlag/Wien 2003
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L. Zecca et al.
phylogenetically close to man, including chimpanzee, gibbon and baboon, and more distant ones, including horse and sheep (Adler, 1942; Marsden, 1961; Cozzi and Tozzi, 1985). Histochemical studies on human SN and LC demonstrated that the pigment displayed proprieties of melanins (Van Woert and Ambani, 1974; Barden, 1975) including insolubility in organic solvents, bleaching by hydrogen peroxide, and labeling by silver stain (Foley and Baxter, 1958). The pigment was therefore named neuromelanin (NM). Histological studies showed that NM granules are located in the neuronal perikaryon and are surrounded by a double membrane (Duffy and Tennyson, 1965; Moses et al., 1966; Hirosawa, 1968). In man and horse, histochemical analyses indicated an association of NM granules with lipofuscin (Barden, 1969; Cozzi et al., 1988). In SN, NM accumulates during aging (Cotzias et al., 1964; Mann and Yates, 1974; Bogerts, 1981; Graham, 1979) and is observed after the first 2-3 years of life (Cowen, 1986). Parkinson's Disease (PD) is a neurodegenerative disorder caused by selective death of pigmented SN neurons (Kastner et al., 1992; Gibb, 1992), giving rise to dopamine depletion in neostriatum (Hornykiewicz, 1986; Bernheimer et al., 1973) and resulting in a clinical syndrome characteried by tremor, rigidity and severely
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