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

Luigi Zecca, Antonella Stroppolo, Alberto Gatti, Davide Tampellini, Marco Toscani, Mario Gallorini, Giuseppe Giaveri, Paolo Arosio, Paolo Santambrogio, Ruggero G. Fariello, Erdem Karatekin, Mark H. Kleinman, Nicholas Turro, Oleh Hornykiewicz, Fabio A. Zucca

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Abstract

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 copper/zinc-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 ferritin/iron 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 copper/zinc-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.

Original languageEnglish
Pages (from-to)9843-9848
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number26
DOIs
Publication statusPublished - Jun 29 2004

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Locus Coeruleus
Substantia Nigra
Iron
Copper
Apoferritins
Superoxide Dismutase
Neurons
Ceruloplasmin
Ferritins
Neuroglia
Parkinson Disease
Zinc
Noxae
Parkinsonian Disorders
Brain Stem

ASJC Scopus subject areas

  • Genetics
  • General

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The role of iron and molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. / Zecca, Luigi; Stroppolo, Antonella; Gatti, Alberto; Tampellini, Davide; Toscani, Marco; Gallorini, Mario; Giaveri, Giuseppe; Arosio, Paolo; Santambrogio, Paolo; Fariello, Ruggero G.; Karatekin, Erdem; Kleinman, Mark H.; Turro, Nicholas; Hornykiewicz, Oleh; Zucca, Fabio A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 26, 29.06.2004, p. 9843-9848.

Research output: Contribution to journalArticle

Zecca, L, Stroppolo, A, Gatti, A, Tampellini, D, Toscani, M, Gallorini, M, Giaveri, G, Arosio, P, Santambrogio, P, Fariello, RG, Karatekin, E, Kleinman, MH, Turro, N, Hornykiewicz, O & Zucca, FA 2004, 'The role of iron and molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 26, pp. 9843-9848. https://doi.org/10.1073/pnas.0403495101
Zecca, Luigi ; Stroppolo, Antonella ; Gatti, Alberto ; Tampellini, Davide ; Toscani, Marco ; Gallorini, Mario ; Giaveri, Giuseppe ; Arosio, Paolo ; Santambrogio, Paolo ; Fariello, Ruggero G. ; Karatekin, Erdem ; Kleinman, Mark H. ; Turro, Nicholas ; Hornykiewicz, Oleh ; Zucca, Fabio A. / The role of iron and molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 26. pp. 9843-9848.
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AU - Zecca, Luigi

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AU - Gatti, Alberto

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AU - Toscani, Marco

AU - Gallorini, Mario

AU - Giaveri, Giuseppe

AU - Arosio, Paolo

AU - Santambrogio, Paolo

AU - Fariello, Ruggero G.

AU - Karatekin, Erdem

AU - Kleinman, Mark H.

AU - Turro, Nicholas

AU - Hornykiewicz, Oleh

AU - Zucca, Fabio A.

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N2 - 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 copper/zinc-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 ferritin/iron 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 copper/zinc-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.

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