Journal of neurochemistry
J Neurochem 2021 Aug; 158(4):960-979
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 H
Vecchio, Laura M; Sullivan, Patricia; Dunn, Amy R; Bermejo, Marie Kristel; Fu, Rong; Masoud, Shababa T; Gregersen, Emil; Urs, Nikhil M; Nazari, Reza; Jensen, Poul Henning; Ramsey, Amy; Goldstein, David S; Miller, Gary W; and Salahpour, Ali, "Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo." (2021). Faculty Research 2021. 167.