Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo

• Type of Material: Article
• Authors: Laura M Vecchio, University of Toronto; Patricia Sullivan, National Institutes of Health, Bethesda; Amy R Dunn, Jackson Laboratory; Marie Kristek Bermejo, University of Toronto; Rong Fu, Emory University; Shababa T Masoud, University of Toronto; Emil Gregersen, Aarhus University; Nikhil M Urs, University of Florida; Reza Nazari, University of Toronto; Poul H Jensen, Aarhus University; Amy Ramsey, University of Toronto; David S Goldstein, National Institutes of Health, Bethesda; Gary Miller, Emory University; Ali Salahpour, University of Toronto
• Language: English
• Date: 2021-06-12
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/jnc.15432
• Title of Journal or Parent Work: JOURNAL OF NEUROCHEMISTRY
• Volume: 158
• Issue: 4
• Start Page: 960
• End Page: 979
• Keywords: MICE LACKING; oxidative stress; GENE-EXPRESSION; DOPAMINE TRANSPORTER; ALPHA-SYNUCLEIN OLIGOMERS; DOPAL; dopamine; PROTEIN PHOSPHATASE 2A; Biochemistry & Molecular Biology; Neurosciences & Neurology; Science & Technology; TIME QUANTITATIVE PCR; tyrosine hydroxylase; SYNAPTIC VESICLES; VESICULAR MONOAMINE TRANSPORTER-2; Life Sciences & Biomedicine; amphetamine; TRANSGENE COPY NUMBER; PARKINSONS-DISEASE; Neurosciences
• Research Categories: Environmental Sciences; Health Sciences, Pharmacology

Abstract

In Parkinson's disease, dopamine-containing nigrostriatal neurons undergo profound degeneration. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine biosynthesis. TH increases in vitro formation of reactive oxygen species, and previous animal studies have reported links between cytosolic dopamine build-up and oxidative stress. To examine effects of increased TH activity in catecholaminergic neurons in vivo, we generated TH-over-expressing mice (TH-HI) using a BAC-transgenic approach that results in over-expression of TH with endogenous patterns of expression. The transgenic mice were characterized by western blot, qPCR, and immunohistochemistry. Tissue contents of dopamine, its metabolites, and markers of oxidative stress were evaluated. TH-HI mice had a 3-fold increase in total and phosphorylated TH levels and an increased rate of dopamine synthesis. Coincident with elevated dopamine turnover, TH-HI mice showed increased striatal production of H2O2 and reduced glutathione levels. In addition, TH-HI mice had elevated striatal levels of the neurotoxic dopamine metabolites 3,4-dihydroxyphenylacetaldehyde and 5-S-cysteinyl-dopamine and were more susceptible than wild-type mice to the effects of amphetamine and methamphetamine. These results demonstrate that increased TH alone is sufficient to produce oxidative stress in vivo, build up autotoxic dopamine metabolites, and augment toxicity. (Figure presented.).