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

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

Tyrosine 3-Monooxygenase
Manganese
Proteins
Dopamine
Phosphotransferases
Phosphorylation
Small Interfering RNA
Neurons
Chemical activation
Degradation

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

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.

In: Neurotoxicity Research, Vol. 32, No. 4, 01.11.2017, p. 661-670.

Research output: Contribution to journalArticle

Kumasaka, MY, 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, vol. 32, no. 4, pp. 661-670. https://doi.org/10.1007/s12640-017-9783-0
Kumasaka, Mayuko Y. ; Yajima, Ichiro ; Ohgami, Nobutaka ; Ninomiya, Hiromasa ; Iida, Machiko ; Li, Xiang ; Oshino, Reina ; Tanihata, Hiroko ; Yoshinaga, Masafumi ; Kato, Masashi. / Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro. In: Neurotoxicity Research. 2017 ; Vol. 32, No. 4. pp. 661-670.
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