Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome |
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Authors: | M Shamoto-Nagai W Maruyama H Yi Y Akao F Tribl M Gerlach T Osawa P Riederer M Naoi |
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Institution: | (1) Department of Geriatric Medicine, National Institute for Geriatrics and Gerontology, Obu, Aichi, Japan;(2) Department of Neurosciences, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan;(3) Department of Psychiatry and Psychotherapy, Clinical Neurochemistry and NPF Center of Excellence Laboratories, Würzburg, Germany;(4) Laboratory of Clinical Neurochemistry, Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany;(5) Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya, Aichi, Japan |
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Abstract: | Summary. Parkinson’s disease is characterized by the selective depletion of dopamine neurons in the substantia nigra, particular those
containing neuromelanin. Involvement of neuromelanin in the pathogenesis may be either cytotoxic or protective. Recently we
found that neuromelanin reduces the activity of 26S proteasome. In this paper, the detailed mechanisms behind the reduced
activity were studied using neuromelanin isolated from the human brain. Neuromelanin increased the oxidative stress, but synthetic
melanin did not. Superoxide dismutase and deferoxamine completely suppressed the increase, indicating that superoxide produced
by an iron-mediated reaction plays a central role. Iron was shown to reduce in situ 26S proteasome activity in SH-SY5Y cells and the reduction was protected by antioxidants. These results suggest that iron
released from neuromelanin increases oxidative stress in mitochondria, and then causes mitochondrial dysfunction and reduces
proteasome function. The role of neuromelanin is discussed in relation to the selective vulnerability of dopamine neurons
in Parkinson’s disease. |
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Keywords: | : Neuromelanin mitochondria oxidative stress Parkinson’ s disease ubiquitin-proteasome system ferrous iron |
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