Metabolism of 3-nitrotyrosine induces apoptotic death in dopaminergic cells

J Neurosci. 2006 Jun 7;26(23):6124-30. doi: 10.1523/JNEUROSCI.1038-06.2006.

Abstract

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 alpha-tubulin. In NT2 cells, incorporation of 3-nitrotyrosine into alpha-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 micromol 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Transport Systems / metabolism
  • Animals
  • Apoptosis / physiology*
  • Aromatic-L-Amino-Acid Decarboxylases / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Cell Physiological Phenomena*
  • Cell Survival
  • Cells / metabolism*
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Humans
  • Mesencephalon / cytology
  • Microtubules / ultrastructure
  • Monoamine Oxidase / metabolism
  • Neurons / physiology
  • Nitrophenols / metabolism
  • PC12 Cells
  • Phenylacetates
  • Rats
  • Tubulin / metabolism
  • Tyrosine / analogs & derivatives*
  • Tyrosine / metabolism

Substances

  • Amino Acid Transport Systems
  • Dopamine Plasma Membrane Transport Proteins
  • Nitrophenols
  • Phenylacetates
  • Tubulin
  • 4-hydroxy-5-nitrophenyl acetic acid
  • 3-nitrotyrosine
  • Tyrosine
  • Monoamine Oxidase
  • Aromatic-L-Amino-Acid Decarboxylases
  • Dopamine