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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.

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|July 22, 2017
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Summary
This summary is machine-generated.

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.

Keywords:
ManganeseMetalsProtein expressionRETTyrosine kinase

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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.