Interaction of neuromelanin and iron in substantia nigra and other areas of human brain

Zecca, Luigi; Shima, Toshihide; Stroppolo, Antonella; Goj, Carlo; Battiston, Giovanni A.; Gerbasi, R.; Sarna, Tadeusz; Swartz, Harold M.

doi:10.1016/0306-4522(96)00047-4

Cited by 181 publications

(187 citation statements)

References 25 publications

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“…The levels of iron in LC were constant throughout life, whereas iron in SN increases in aging (17). Iron deposits histochemically detectable are absent in NM neurons of SN, in agreement with previous studies (22,28), and are due to the ability of NM in scavenging iron to form the complex NM-iron. The density of iron deposits observed by histochemistry in LC is also much lower than that in SN, thus paralleling the difference in total iron concentration between LC and SN measured by electrothermal atomic absorption spectroscopy and neutron activation analysis.…”

Section: Discussion Iron Content In Lc Is Much Lower Than That Of Sn supporting

confidence: 91%

“…The content of iron, copper, NM, ferritins, Cp, copper͞ zinc-SOD, and manganese-SOD in LC are reported here. The most striking finding is the very low concentration of iron measured in LC, which is much lower than that found in SN and other brain regions, such as basal ganglia nuclei (14,15,17,22). The levels of iron in LC were constant throughout life, whereas iron in SN increases in aging (17).…”

Section: Discussion Iron Content In Lc Is Much Lower Than That Of Sn mentioning

confidence: 84%

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The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

Zecca

Stroppolo

Gatti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

433

469

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In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper͞zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin͞iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy-and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper͞zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. L ocus coeruleus (LC) is the main brain region containing norepinephrine neurons. The rostral projections from these neurons seem to be involved in the modulation of neuronal activity, metabolism, and memory (1, 2), whereas the spinal cord projections are known to modulate spinal motoneuron function (3, 4).Neuronal loss in LC occurs in conditions such as Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome (5, 6) with different cellular loss in rostral and caudal parts of LC. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In idiopathic PD, most studies have documented a higher degree of neuronal loss in substantia nigra (SN) compared to LC (5-8). However, a recent study reported extensive impairment of LC neurons in PD (9). SN and LC share anatomical and biochemical similarities, being both pigmented because of neuromelanin (NM), and both composed of catecholaminergic neurons. Yet, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineintoxicated subjects, LC neurons are spared, whereas a large neuronal depletion occurs in SN (10, 11). Also, in other types of Parkinsonian syndromes caused by exposure to toxins, the LC neurons seem less damaged than those of...

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Section: Discussion Iron Content In Lc Is Much Lower Than That Of Sn supporting

confidence: 91%

Section: Discussion Iron Content In Lc Is Much Lower Than That Of Sn mentioning

confidence: 84%

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

Zecca

Stroppolo

Gatti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

433

469

View full text Add to dashboard Cite

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“…Eumelanin is characterized by dihydroxyindole groups formed by DA oxidation and is responsible for the metal-chelating ability of neuromelanin (14). Pheomelanin is generated by oxidation of cysteinyl-dopamine (Cys-DA) and contains benzothiazine groups.…”

mentioning

confidence: 99%

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

Zecca

Bellei²,

Costi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

211

355

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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

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“…There are a number of possible sources of toxic ROS in PD brain. Aberrant availability of redox active iron in neurons may be the primary source, whether it's cytosolic or compartmentalized, as for example in neuromelanin [20]. Because dopaminergic cells are uniquely vulnerable to degenerate, dopamine may provide a source for hydroxyl radical generation.…”

Section: +mentioning

confidence: 99%

Oxidative Stress in Parkinson`s Disease

Friedlich

Smith²,

Zhu³

et al. 2009

TOPATJ

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Abstract:Parkinson's disease (PD) is a progressive, age-related movement disorder, whose neuropathology is characterized by degeneration of the afferent pigmented neurons of the substantia nigra. Also associated with PD neuropathology are disrupted iron homeostasis, oxidative stress, and intracellular deposition of alpha-synuclein protein in Lewy bodies. Here we review oxidative stress mechanisms in Parkinson's disease, with emphasis on the relationship between oxidative stress and alpha-synuclein gene expression.

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Interaction of neuromelanin and iron in substantia nigra and other areas of human brain

Cited by 181 publications

References 25 publications

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

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

Oxidative Stress in Parkinson`s Disease

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