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J. Biol. Chem., Vol. 283, Issue 50, 34887-34895, December 12, 2008

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Formation of Dopamine Adducts Derived from Brain Polyunsaturated Fatty Acids

MECHANISM FOR PARKINSON DISEASE^*

Xuebo Liu¹, Naruomi Yamada¹, Wakako Maruyama, and Toshihiko Osawa²

From the Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Science, Nagoya University, Nagoya 464-8601, Japan and the Department of Basic Gerontology, National Institute for Longevity Science, Obu 474-8522, Japan

Oxidative stress appears to be directly involved in the pathogenesis of the neurodegeneration of dopaminergic systems in Parkinson disease. In this study, we formed four dopamine modification adducts derived from docosahexaenoic acid (C22:6/-3) and arachidonic acid (C18:4/-6), which are known as the major polyunsaturated fatty acids in the brain. Upon incubation of dopamine with fatty acid hydroperoxides and an in vivo experiment using rat brain tissue, all four dopamine adducts were detected. Furthermore, hexanoyl dopamine (HED), an arachidonic acid-derived adduct, caused severe cytotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells, whereas the other adducts were only slightly affected. The HED-induced cell death was found to include apoptosis, which also seems to be mediated by reactive oxygen species generation and mitochondrial abnormality. Additionally, the experiments using monoamine transporter inhibitor and mouse embryonic fibroblast NIH-3T3 cells that lack the monoamine transporter indicate that the HED-induced cytotoxicity might specially occur in the neuronal cells. These data suggest that the formation of the docosahexaenoic acid- and arachidonic acid-derived dopamine adducts in vitro and in vivo, and HED, the arachidonic acid-derived dopamine modification adduct, which caused selective cytotoxicity of neuronal cells, may indicate a novel mechanism responsible for the pathogenesis in Parkinson disease.

Received for publication, July 24, 2008 , and in revised form, October 8, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. Fax: 81-52-789-5741; E-mail: osawat{at}agr.nagoya-u.ac.jp.

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