学術雑誌論文 Manganese-mediated decrease in levels of c-RET and tyrosine hydroxylase expression in vitro

Kumasaka, Mayuko Y.  ,  Yajima, Ichiro  ,  Ohgami, Nobutaka  ,  Ninomiya, Hiromasa  ,  Iida, Machiko  ,  Li, Xiang  ,  Oshino, Reina  ,  Tanihata, Hiroko  ,  Yoshinaga, Masafumi  ,  Kato, Masashi

32 ( 4 )  , pp.661 - 670 , 2017-11 , Springer
ISSN:1029-8428
内容記述
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 our knowledge, however, there is no report showing a correlation between manganese-mediated parkinsonism and c-RET. In this study, we examined the effect of manganese on the expression and/or activation levels of c-RET and TH in human TH-expressing cells (TGW cells). We first found that treatment with 30 and 100 μM manganese resulted in reduction of c-RET transcript level and degradation of c-RET protein through promotion of ubiquitination. We then examined the biological significance of manganese-mediated decrease of c-RET protein expression. Decreased TH expression with decreased c-RET kinase activity was observed in c-RET protein-depleted TGW cells by treatment with manganese (30 μM) 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, our 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.
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