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The Journal of Neuroscience, June 7, 2006, 26(23):6124-6130; doi:10.1523/JNEUROSCI.1038-06.2006

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Neurobiology of Disease
Metabolism of 3-Nitrotyrosine Induces Apoptotic Death in Dopaminergic Cells

Béatrice Blanchard-Fillion,¹ Delphine Prou,² Manuela Polydoro,¹ David Spielberg,¹ Elpida Tsika,¹ Zeneng Wang,⁵ Stanley L. Hazen,⁵ Michael Koval,⁶ Serge Przedborski,^2,3,4 and Harry Ischiropoulos^1,7

¹Stokes Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, Departments of ²Neurology and ³Pathology and Cell Biology and ⁴Center of Neurobiology and Behavior, Columbia University, New York, New York 10032, ⁵Department of Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and Departments of ⁶Physiology and ⁷Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Harry Ischiropoulos, Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Research Center, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399. Email: ischirop{at}mail.med.upenn.edu

Intrastriatal injection of 3-nitrotyrosine, which is a biomarker for nitrating oxidants, provokes dopaminergic neuronal death in rats by unknown mechanisms. Herein, we show that extracellular 3-nitrotyrosine is transported via the L-aromatic amino acid transporter in nondopaminergic NT2 cells, whereas in dopaminergic PC12 cells, it is transported by both the l-aromatic amino acid and the dopamine transporters. In both cell lines, 3-nitrotyrosine is a substrate for tyrosine tubulin ligase, resulting in its incorporation into the C terminus of -tubulin. In NT2 cells, incorporation of 3-nitrotyrosine into -tubulin induces a progressive, reversible reorganization of the microtubule architecture. In PC12 cells, 3-nitrotyrosine decreases intracellular dopamine levels and is metabolized by the concerted action of the aromatic amino acid decarboxylase and monoamine oxidase. Intracellular levels of 133 µmol of 3-nitrotyrosine per mole of tyrosine did not alter NT2 viability but induced PC12 apoptosis. The cell death was reversed by caspases and aromatic amino acid decarboxylase and monoamine oxidase inhibitors. 3-Nitrotyrosine induced loss of tyrosine hydroxylase-positive primary rat neurons, which was also prevented by an aromatic amino acid decarboxylase inhibitor. These findings provide a novel mechanism by which products generated by reactive nitrogen species induce dopaminergic neuron death and thus may contribute to the selective neurodegeneration in Parkinson's disease.

Key words: dopamine; neurotoxicity; aromatic amino acid decarboxylase; monoamine oxidase; reactive nitrogen species; nitration; tubulin

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Received Nov. 8, 2005; accepted April 6, 2006.

Correspondence should be addressed to Dr. Harry Ischiropoulos, Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Research Center, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399. Email: ischirop{at}mail.med.upenn.edu

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				L. D. Rankin, D. M. Bodenmiller, J. D. Partridge, S. F. Nishino, J. C. Spain, and S. Spiro Escherichia coli NsrR Regulates a Pathway for the Oxidation of 3-Nitrotyramine to 4-Hydroxy-3-Nitrophenylacetate J. Bacteriol., September 15, 2008; 190(18): 6170 - 6177. [Abstract] [Full Text] [PDF]

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