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The roles of neuromelanin, binding of metal ions, and oxidative cytotoxicity in the pathogenesis of Parkinson's disease: A hypothesis

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Journal of Neural Transmission - Parkinson's Disease and Dementia Section

Summary

A characteristic feature of both Parkinson's disease (idiopathic paralysis agitans) and normal aging is loss of pigmented neurons in the substantia nigra. This has been found to correlate with the accumulation of neuromelanin and with oxidative stress in this brain region, but a clear association between these factors has not been established. Based on our recent demonstration that neuromelanin is a true melanin, containing bound metal ions in situ, we present a general model for its accumulation in vivo and the hypotheses (1) that it has a cytoprotective function in the sequestration of redox-active metal ions under normal conditions but (2) that it has a cytotoxic role in the pathogenesis of Parkinson's disease. Thus, neuromelanin accumulates normally through the autooxidation of catecholamines and serves tightly to bind redox-active metal ions, processes which would accelerate under conditions of intracellular or extracellular oxidative stress. Based on the known properties of melanin, however, neuromelanin also has the potential for exacerbating oxidative stress, eg by generating H2O2 when it is intact or by releasing redox-active metal ions if it loses its integrity; these reactions also would modulate the reactivity of the neuromelanin. By overwhelming intracellular antioxidative defense mechanisms, such a positive-feedback cycle could turn a condition of chronic or repeated oxidative stress in vulnerable neurons into an acute crisis, leading to cellular death. If the cumulative stress in duration and/or degree is severe enough, neuronal depletion could be sufficient to cause Parkinson's disease during life. One possible trigger for this cascade is suggested by the increased nigral iron contents in postmortem parkinsonian brains and the correlation of this disease with urban living where exposure to heavy metal ions is high: the saturation of neuromelanin with redox-active metal ions. Parkinson's disease therefore may be a form of accelerated aging in the substantia nigra associated with environmental toxins in which neuromelanin has a central, active role.

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Author notes

  1. H. M. Swartz M.D., Ph. D.

    Present address: Dartmouth Medical School, 7252 Strasenburgh Hall, Rm 308, 03755-3863, Hanover, NH, U.S.A

Authors and Affiliations

  1. University of Illinois College of Medicine, Urbana, IL

    W. S. Enochs & H. M. Swartz M.D., Ph. D.

  2. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, U.S.A.

    W. S. Enochs

  3. Jagellonian University, Krakow, Poland

    T. Sarna

  4. Istituto Technologie Biomediche Avanzate, CNR, Milano, Italy

    L. Zecca

  5. University of London, London, UK

    P. A. Riley

Authors
  1. W. S. Enochs
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  2. T. Sarna
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  3. L. Zecca
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  4. P. A. Riley
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  5. H. M. Swartz M.D., Ph. D.
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Enochs, W.S., Sarna, T., Zecca, L. et al. The roles of neuromelanin, binding of metal ions, and oxidative cytotoxicity in the pathogenesis of Parkinson's disease: A hypothesis. J Neural Transm Gen Sect 7, 83–100 (1994). https://doi.org/10.1007/BF02260963

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  • DOI: https://doi.org/10.1007/BF02260963

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