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The Journal of Neuroscience, November 11, 2009, 29(45):14057-14065; doi:10.1523/JNEUROSCI.3890-09.2009

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Neurobiology of Disease
Ghrelin Promotes and Protects Nigrostriatal Dopamine Function via a UCP2-Dependent Mitochondrial Mechanism

Zane B. Andrews,^1,2,10 Derek Erion,² Rudolph Beiler,¹ Zhong-Wu Liu,² Alfonso Abizaid,⁹ Jeffrey Zigman,⁵ John D. Elsworth,³ Joseph M. Savitt,⁶ Richard DiMarchi,⁷ Matthias Tschöp,⁸ Robert H. Roth,^3,4 Xiao-Bing Gao,² and Tamas L. Horvath^1,2,4

¹Section of Comparative Medicine and ²Departments of Obstetrics, Gynecology & Reproductive Sciences, ³Psychiatry, and ⁴Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, ⁵Division of Hypothalamic Research and Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9077, ⁶Department of Neurology and Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland 21287-7619, ⁷Department of Chemistry and Biochemistry Program, Indiana University, Bloomington, Indiana 47405, ⁸Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45221-0001, ⁹Department of Psychology, Carleton University, Ottawa K1S 5B6, Canada, and ¹⁰Department of Physiology, Monash University, Clayton, Victoria 3183, Australia

Correspondence should be addressed to Tamas L. Horvath at the above address. Email: tamas.horvath{at}yale.edu

Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.

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Received Aug. 9, 2009; revised Sept. 1, 2009; accepted Sept. 15, 2009.

Correspondence should be addressed to Tamas L. Horvath at the above address. Email: tamas.horvath{at}yale.edu

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