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

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

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4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)661-670
Number of pages10
JournalNeurotoxicity Research
Volume32
Issue number4
DOIs
Publication statusPublished - 2017 Nov 1

Keywords

  • Manganese
  • Metals
  • Protein expression
  • RET
  • Tyrosine kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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    Kumasaka, M. Y., Yajima, I., Ohgami, N., Ninomiya, H., Iida, M., Li, X., Oshino, R., Tanihata, H., Yoshinaga, M., & Kato, M. (2017). Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro. Neurotoxicity Research, 32(4), 661-670. https://doi.org/10.1007/s12640-017-9783-0