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The Journal of Neuroscience, January 5, 2005, 25(1):184-191; doi:10.1523/JNEUROSCI.4269-04.2005

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Neurobiology of Disease
Uncoupling Protein-2 Is Critical for Nigral Dopamine Cell Survival in a Mouse Model of Parkinson's Disease

Zane B. Andrews,¹ Balazs Horvath,² Colin J. Barnstable,^2,3 John Elseworth,⁴ Lichuan Yang,⁵ M. Flynt Beal,⁵ Robert H. Roth,⁴ Russell T. Matthews,² and Tamas L. Horvath^1,2

Departments of ¹Obstetrics, Gynecology, and Reproductive Sciences, ²Neurobiology, ³Ophthalmology-Visual Science, and ⁴Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, and ⁵Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021

Mitochondrial uncoupling proteins dissociate ATP synthesis from oxygen consumption in mitochondria and suppress free-radical production. We show that genetic manipulation of uncoupling protein-2 (UCP2) directly affects substantia nigra dopamine cell function. Overexpression of UCP2 increases mitochondrial uncoupling, whereas deletion of UCP2 reduces uncoupling in the substantia nigra-ventral tegmental area. Overexpression of UCP2 decreased reactive oxygen species (ROS) production, which was measured using dihydroethidium because it is specifically oxidized to fluorescent ethidium by the superoxide anion, whereas mice lacking UCP2 exhibited increased ROS relative to wild-type controls. Unbiased electron microscopic analysis revealed that the elevation of in situ mitochondrial ROS production in UCP2 knock-out mice was inversely correlated with mitochondria number in dopamine neurons. Lack of UCP2 increased the sensitivity of dopamine neurons to 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP), whereas UCP2 overexpression decreased MPTP-induced nigral dopamine cell loss. The present results expose the critical importance of UCP2 in normal nigral dopamine cell metabolism and offer a novel therapeutic target, UCP2, for the prevention/treatment of Parkinson's disease.

Key words: uncoupling protein-2; mitochondria; reactive oxygen species; substantia nigra; MPTP; Parkinson's disease

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Received Aug 2, 2004; revised November 10, 2004; accepted November 11, 2004.

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