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Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro
Mayuko Y Kumasaka1,2,3, Ichiro Yajima1,2,3, Nobutaka Ohgami1,2,3
1Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
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.
Insights
Manganese exposure reduces c-RET protein, leading to decreased tyrosine hydroxylase (TH) expression. This suggests a novel mechanism linking manganese-induced parkinsonism to the c-RET/TH pathway in neural cells.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese overexposure is linked to parkinsonism, a neurodegenerative disorder affecting dopaminergic neurons.
- c-RET kinase activity regulates dopamine production via tyrosine hydroxylase (TH) expression, implicating c-RET in parkinsonism.
- The specific link between manganese-induced parkinsonism and c-RET remains underexplored.
Purpose of the Study:
- To investigate the effect of manganese on c-RET and TH expression and activation in human TH-expressing cells (TGW cells).
- To elucidate the role of c-RET in manganese-mediated neurotoxicity and parkinsonism development.
Main Methods:
- Treatment of TGW cells with varying concentrations of manganese (30 and 100 μM).
- Analysis of c-RET transcript and protein levels, including ubiquitination.
- Assessment of TH expression and c-RET kinase activity in manganese-treated and c-RET siRNA-transfected cells.
Main Results:
- Manganese treatment (30 and 100 μM) reduced c-RET transcript levels and promoted c-RET protein degradation via ubiquitination.
- Depletion of c-RET protein (via manganese or siRNA) led to decreased TH expression and reduced c-RET kinase activity.
- These findings suggest manganese impacts the dopamine-producing pathway through c-RET downregulation.
Conclusions:
- Manganese exposure decreases c-RET expression and activity in neural cells.
- Reduced c-RET leads to decreased TH expression, potentially contributing to dopamine deficiency in manganese-induced parkinsonism.
- This study identifies a novel molecular pathway involved in manganese neurotoxicity and parkinsonism.
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