PT  - JOURNAL ARTICLE
AU  - Béatrice Blanchard-Fillion
AU  - Delphine Prou
AU  - Manuela Polydoro
AU  - David Spielberg
AU  - Elpida Tsika
AU  - Zeneng Wang
AU  - Stanley L. Hazen
AU  - Michael Koval
AU  - Serge Przedborski
AU  - Harry Ischiropoulos
TI  - Metabolism of 3-Nitrotyrosine Induces Apoptotic Death in Dopaminergic Cells
AID  - 10.1523/JNEUROSCI.1038-06.2006
DP  - 2006 Jun 07
TA  - The Journal of Neuroscience
PG  - 6124--6130
VI  - 26
IP  - 23
4099  - http://www.jneurosci.org/content/26/23/6124.short
4100  - http://www.jneurosci.org/content/26/23/6124.full
SO  - J. Neurosci.2006 Jun 07; 26
AB  - 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 α-tubulin. In NT2 cells, incorporation of 3-nitrotyrosine into α-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.