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Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line
Danhui Zhang1, Arthi Kanthasamy, Vellareddy Anantharam
1Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011-1250, USA.
Abstract:
Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson's disease. However, the cellular mechanism by which Mn impairs the dopaminergic neurotransmitter system remains unclear. We previously demonstrated that caspase-3-dependent proteolytic activation of protein kinase C delta (PKCδ) plays a key role in Mn-induced apoptotic cell death in dopaminergic neurons. Recently, we showed that PKCδ negatively regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, by enhancing protein phosphatase-2A activity in dopaminergic neurons. Here, we report that Mn exposure can affect the enzymatic activity of TH, the rate-limiting enzyme in dopamine synthesis, by activating PKCδ-PP2A signaling pathway in a dopaminergic cell model. Low dose Mn (3-10microM) exposure to differentiated mesencephalic dopaminergic neuronal cells for 3h induced a significant increase in TH activity and phosphorylation of TH-Ser40. The PKCδ specific inhibitor rottlerin did not prevent Mn-induced TH activity or TH-Ser40 phosphorylation. On the contrary, chronic exposure to 0.1-1 microM Mn for 24h induced a dose-dependent decrease in TH activity. Interestingly, chronic Mn treatment significantly increased PKCδ kinase activity and protein phosphatase 2A (PP2A) enzyme activity. Treatment with the PKCδ inhibitor rottlerin almost completely prevented chronic Mn-induced reduction in TH activity, as well as increased PP2A activity. Neither acute nor chronic Mn exposures induced any cytotoxic cell death or altered TH protein levels. Collectively, these results demonstrate that low dose Mn exposure impairs TH activity in dopaminergic cells through activation of PKCδ and PP2A activity.
Insights
Manganese (Mn) exposure impacts tyrosine hydroxylase (TH) activity in dopaminergic cells. Chronic Mn exposure impairs TH via the protein kinase C delta (PKCδ) and protein phosphatase 2A (PP2A) pathway, without causing cell death.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese (Mn) exposure leads to manganism, a Parkinson's-like neurological disorder.
- The precise cellular mechanisms of Mn neurotoxicity, particularly its effects on dopaminergic neurons, are not fully understood.
- Previous research implicated caspase-3-dependent activation of protein kinase C delta (PKCδ) in Mn-induced dopaminergic neuron apoptosis.
Purpose of the Study:
- To investigate the effect of manganese exposure on tyrosine hydroxylase (TH) activity in dopaminergic cells.
- To elucidate the role of the PKCδ-protein phosphatase 2A (PP2A) signaling pathway in Mn-induced alterations of TH activity.
Main Methods:
- Differentiated mesencephalic dopaminergic neuronal cells were exposed to varying doses of Mn (acute: 3-10µM for 3h; chronic: 0.1-1µM for 24h).
- TH enzymatic activity, TH-Ser40 phosphorylation, PKCδ kinase activity, and PP2A enzyme activity were measured.
- The specific PKCδ inhibitor rottlerin was used to assess its effects on Mn-induced changes.
Main Results:
- Acute low-dose Mn exposure transiently increased TH activity and TH-Ser40 phosphorylation, unaffected by rottlerin.
- Chronic Mn exposure dose-dependently decreased TH activity and increased both PKCδ and PP2A activities.
- Rottlerin treatment prevented the chronic Mn-induced reduction in TH activity and the increase in PP2A activity.
- Neither acute nor chronic Mn exposure resulted in cytotoxicity or altered TH protein levels.
Conclusions:
- Chronic manganese exposure impairs dopaminergic neuron function by reducing TH activity through the activation of the PKCδ-PP2A signaling pathway.
- This pathway modulates TH activity without affecting TH protein levels or causing cell death, highlighting a specific mechanism of neurotoxicity.
- Targeting the PKCδ-PP2A pathway may offer therapeutic strategies for manganism and related neurodegenerative conditions.
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