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

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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.

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Acknowledgements

This study was supported in part by the Grants-in-Aid for Scientific Research (A) (15H01743 and 15H02588) and (B) (16H02962, 24390157 and 24406002) and (C) (No. 25460178, 25340052, 16K10152, 16K08343), Grant-in-Aid for Challenging Exploratory Research (26670525), Grant-in-Aid for Scientific Research on Innovative Areas (24108001), Grants-in-Aid for Scientific Research on Innovative Areas (16H01639), and Grant-in-Aid for Research Activity Start-up (15H06274) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Foundation from Center for Advanced Medical and Clinical Research of Nagoya University Hospital, The Mitsubishi Foundation, The Salt Science Research Foundation, Aichi Health Promotion Foundation, AEON Environmental Foundation, Nagono Medical Foundation, Grant for Environmental Research Projects from the Sumitomo Foundation (163119), Ichihara International Scholarship Foundation, and the KENKO-KAGAKU Zaidan (Health Sciences Foundation).

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Authors and Affiliations

  1. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan

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

  2. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, 487-8501, Japan

    Mayuko Y. Kumasaka, Ichiro Yajima, Nobutaka Ohgami, Machiko Iida & Masashi Kato

  3. Voluntary Body for International Health Care in Universities, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Mayuko Y. Kumasaka, Ichiro Yajima, Nobutaka Ohgami, Hiromasa Ninomiya, Machiko Iida, Reina Oshino, Masafumi Yoshinaga & Masashi Kato

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  1. Mayuko Y. Kumasaka
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  2. Ichiro Yajima
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  3. Nobutaka Ohgami
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  4. Hiromasa Ninomiya
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  6. Xiang Li
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  8. Hiroko Tanihata
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  9. Masafumi Yoshinaga
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  10. Masashi Kato
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Correspondence to Masashi Kato.

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Kumasaka, M.Y., Yajima, I., Ohgami, N. et al. Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro. Neurotox Res 32, 661–670 (2017). https://doi.org/10.1007/s12640-017-9783-0

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