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Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+)

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Studies in post-mortem tissues of patients with Parkinson’s disease (PD) and in mice treated with 6-hydroxydopamine have shown a decrease in the length of axon and dendrites of striatal neurons. However, the etiology of the morphological changes and their relationship to inhibition of mitochondrial complex I and the cellular levels of iron and glutathione (GSH) have not been described. In this study, we characterized the effect of MPP+, an inhibitor of mitochondria complex I, on the integrity of the neuritic tree of midbrain dopaminergic neurons, and determined the influence of iron and cellular levels of GSH on this degeneration. Sub-maximal concentrations of MPP+ induced a drastic dose-dependent reduction of neurites, without modification of the soma or apparent cell death. Concurrent treatment with MPP+ and non-toxic concentrations of iron accelerated the process of degeneration, whereas neurons grown on a medium low in iron showed enhanced resistance to MPP+ treatment. MPP+-induced neurite shortening depended on the redox state of neurons. Pre-treatment with the general antioxidant N-acetyl cysteine protected neurons from degeneration. Treatment with sub-maximal concentrations of the inhibitor of GSH synthesis buthionine sulfoximine (BSO), in conjunction with iron and MPP+, produced massive cell death, whereas treatment with BSO plus MPP+ under low iron conditions did not damage neurons. These results suggest that under conditions of inhibition of mitochondrial complex I caused by MPP+, the accumulation of iron and the concurrent decrease in GSH results in the loss of the dendritic tree prior to cell death, of dopaminergic neurons in PD.

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Acknowledgments

This work was financed by Grant 1100599 from Fondo Nacional de Ciencia y Tecnología Chile, (FONDECYT) and by project ICM-P05-001-F from the Millennium Scientific Initiative, Ministerio de Planificación Nacional (MIDEPLAN).

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Authors and Affiliations

  1. Department of Biology, Faculty of Sciences, Cell Dynamics and Biotechnology Institute, Universidad de Chile, Santiago, Chile

    Francisco J. Gómez, Pabla Aguirre, Christian Gonzalez-Billault & Marco T. Núñez

  2. Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Santiago, Chile

    Marco T. Núñez

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  1. Francisco J. Gómez
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  2. Pabla Aguirre
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Correspondence to Marco T. Núñez.

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Gómez, F.J., Aguirre, P., Gonzalez-Billault, C. et al. Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+). J Neural Transm 118, 421–431 (2011). https://doi.org/10.1007/s00702-010-0489-1

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  • DOI: https://doi.org/10.1007/s00702-010-0489-1

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