Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro

Previous studies showed that overexposure to manganese causes parkinsonism, a disorder of dopaminergic neurons. Previous studies also showed that activity of c-RET kinase controls dopamine production through regulation of tyrosine hydroxylase (TH) expression, suggesting the involvement of c-RET in the development of parkinsonism. To the authors knowledge, however, there is no report showing a correlation between manganese-mediated parkinsonism and c-RET. In this study, the effect of manganese on the expression and/or activation levels of c-RET and TH in human TH-expressing cells (TGW cells) were examined. Firstly, the authors found that treatment with 30 and 100 ?M manganese resulted in reduction of c-RET transcript level and degradation of c-RET protein through promotion of ubiquitination. Then, the biological significance of manganese-mediated decrease of c-RET protein expression was examined. Decreased TH expression with decreased c-RET kinase activity was observed in c-RET protein-depleted TGW cells by treatment with manganese (30 ?M) as well as by c-RET siRNA transfection. Since TH protein has been shown to be involved in the dopamine-producing pathway in previous studies, the results indicate the possibility that manganese-mediated reduction of TH expression and phosphorylation via decreased expression of c-RET protein in neural cells is involved in parkinsonism induced by manganese.

Authors: Kumasaka MY, Yajima I, Ohgami N, Ninomiya H, Iida M, Li X, Oshino R, Tanihata H, Yoshinaga M, Kato M. ; Full Source: Neurotoxicity Research. 2017 Jul 20. doi: 10.1007/s12640-017-9783-0. [Epub ahead of print]