W Maruyama1 M Shamoto Nagai1 Y Akao2 P Riederer3 and M Naoi2

1 Department of Geriatric Medicine, National Institute for Geriatrics and Gerontology,

Obu, Aichi, and

2 Department of Neurosciences, Gifu International Institute for Biotechnology, Kakamigahara, Gifu, Japan 3 Clinical Neurochemistry and NPF Center of Excellence Laboratories, Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

Summary. In Parkinson's disease (PD), the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin (NM), is the characteristic pathological feature. The role of NM in the cell death of dopamine neurons has been considered either to be neurotoxic or neuroprotective, but the precise mechanism has never been elucidated. In human brain, NM is synthesized by polymerization of dopamine and relating quinones, to which bind heavy metals including iron. The effects of NM prepared from human brain were examined using human dopaminergic SH-SY5Y cells. It was found that NM inhibits 26S proteasome activity through generation of reactive oxygen and nitrogen species from mitochondria. The mi-tochondrial dysfunction was also induced by oxidative stress mediated by iron released from NM. NM accumulated in dopamine neurons in ageing may determine the selective vulnerability of dopamine neurons in PD.

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