Journal article
Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
Proceedings of the National Academy of Sciences - PNAS, v 95(13), pp 7659-7663
23 Jun 1998
PMID: 9636206
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
- Creators
- Jahan Ara - Department of Pharmacology, Allegheny University, Philadelphia, PA 10912Serge Przedborski - Department of Pharmacology, Allegheny University, Philadelphia, PA 10912Ali B Naini - Department of Pharmacology, Allegheny University, Philadelphia, PA 10912Vernice Jackson-Lewis - Department of Pharmacology, Allegheny University, Philadelphia, PA 10912Rosario R Trifiletti - Department of Pharmacology, Allegheny University, Philadelphia, PA 10912Joel Horwitz - Department of Pharmacology, Allegheny University, Philadelphia, PA 10912Harry Ischiropoulos - Department of Pharmacology, Allegheny University, Philadelphia, PA 10912
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 95(13), pp 7659-7663
- Publisher
- The National Academy of Sciences
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000074436400076
- Scopus ID
- 2-s2.0-0032560486
- Other Identifier
- 991014878481804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology