INACTIVATION OF TYROSINE-HYDROXYLASE BY NITRATION FOLLOWING EXPOSURE TO PEROXYNITRITE AND 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP)

The decrement in dopamine levels exceeds the loss of dopaminergic neur ons 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-limi ting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is a sel ective 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 pa rallels the decline in dopamine levels whereas the levels of TH protei n remain unchanged for the first 6 hr post MPTP injection. Striatal TH was not nitrated in mice overexpressing copper/zinc superoxide dismut ase after MPTP administration, supporting a critical role for superoxi de in TH tyrosine nitration, These results indicate that tyrosine nitr ation-induced TH inactivation and consequently dopamine synthesis fail ure, represents an early and thus far unidentified biochemical event i n MPTP neurotoxic process. The resemblance of the MPTP model with PD s uggests that a similar phenomenon may occur in PD, influencing the sev erity of parkisonian symptoms.