Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

^*Department of Pharmacology, Allegheny University, Philadelphia, PA 10912; ^†Neuroscience Research, Movement Disorder Division, Department of Neurology, Columbia University, New York, NY 10032; ^§Department of Neurology, Neuroscience and Pediatrics, Cornell University Medical College, New York, NY 10021; and ^¶Stokes Research Institute and Department of Biochemistry and Biophysics, Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA 19104

Edited by Irwin Fridovich, Duke University Medical Center, Durham, NC, and approved April 24, 1998 (received for review March 23, 1998)

Abstract

The decrement in dopamine levels exceeds the loss of dopaminergic neurons in Parkinson’s disease (PD) patients and experimental models of PD. This discrepancy is poorly understood and may represent an important event in the pathogenesis of PD. Herein, we report that the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is a selective target for nitration following exposure of PC12 cells to either peroxynitrite or 1-methyl-4-phenylpyridiniun ion (MPP⁺). Nitration of TH also occurs in mouse striatum after MPTP administration. Nitration of tyrosine residues in TH results in loss of enzymatic activity. In the mouse striatum, tyrosine nitration-mediated loss in TH activity parallels the decline in dopamine levels whereas the levels of TH protein remain unchanged for the first 6 hr post MPTP injection. Striatal TH was not nitrated in mice overexpressing copper/zinc superoxide dismutase after MPTP administration, supporting a critical role for superoxide in TH tyrosine nitration. These results indicate that tyrosine nitration-induced TH inactivation and consequently dopamine synthesis failure, represents an early and thus far unidentified biochemical event in MPTP neurotoxic process. The resemblance of the MPTP model with PD suggests that a similar phenomenon may occur in PD, influencing the severity of parkisonian symptoms.

Footnotes

↵ ‡ To whom correspondence should be addressed. e-mail: ischirop{at}mail.med.upenn.edu and przedbo{at}cudept.cis.columbia.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease; TH, tyrosine hydroxylase; MPP⁺, 1-methyl-4-phenylpyridiniun ion; Cu/Zn, copper/zinc; SOD, superoxide dismutase.