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The Journal of Neuroscience, July 13, 2005, 25(28):6594-6600; doi:10.1523/JNEUROSCI.0970-05.2005

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Neurobiology of Disease
Ablation of the Inflammatory Enzyme Myeloperoxidase Mitigates Features of Parkinson's Disease in Mice

Dong-Kug Choi,^1,5 Subramaniam Pennathur,⁴ Celine Perier,¹ Kim Tieu,¹ Peter Teismann,¹ Du-Chu Wu,¹ Vernice Jackson-Lewis,¹ Miquel Vila,¹ Jean-Paul Vonsattel,² Jay W. Heinecke,⁴ and Serge Przedborski^1,2,3

¹Neuroscience Research Laboratories of the Movement Disorder Division, Department of Neurology, ²Department of Pathology, and ³Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, ⁴Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington 98195, and ⁵Department of Biotechnology, Konkuk University, Chungju-City, Chungbuk 380-701, Korea

Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.

Key words: MPTP; Parkinson's disease; oxidative stress; inflammation; neuroprotection; nitrotyrosine

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Received March 11, 2005; revised May 16, 2005; accepted May 31, 2005.

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