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Microcystin-LR-caused ROS generation involved in p38 activation and tau hyperphosphorylation in neuroendocrine (PC12)
Guanmin Meng1, Jinghui Liu, Shuyan Lin
1Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, 234 Gucui Road, Hangzhou, 310012, China; Department of Biochemistry, School of Medicine, Zhejiang University, 866th Yu Hang Tang Road, Hangzhou, 310058, China.
Abstract:
Microcystin-LR (MC-LR), a potent specific hepatotoxin produced by cyanobacteria, has recently been reported to show neurotoxicity. Our previous study demonstrated that MC-LR caused the reorganization of cytoskeleton architectures and hyperphosphorylation of the cytoskeletal-associated proteins tau and HSP27 in neuroendocrine PC12 cell line by direct PP2A inhibition and indirect p38 mitogen-activated protein kinase (MAPK) activation. It has been shown that oxidative stress is extensively associated with MC-LR toxicity, mainly resulting from an excessive production of reactive oxygen species (ROS). However, the mechanisms by which ROS mediates the cytotoxic action of MC-LR are unclear. In the present study, we investigated whether ROS might play a critical role in MC-LR-induced hyperphosphorylation of microtubule-associated protein tau and the activation of the MAPKs in PC12 cell line. The results showed that MC-LR had time- and concentration-dependent effects on ROS generation, p38-MAPK activation and tau phosphorylation. The time-course studies indicated similar biphasic changes in ROS generation and tau hyperphosphorylation, which started to increase within 1 h and reached the maximum level at 3 h followed by a decrease after prolonged treatment. Furthermore, pretreatment with the antioxidants, N-acetylcysteine and vitamin C, significantly decreased MC-LR-induced ROS generation and effectively attenuated p38-MAPK activation as well as tau hyperphosphorylation. Taken together, these findings suggest that ROS generation triggered by MC-LR is a key intracellular event that contributes to an induction of p38-MAPK activation and tau phosphorylation, and that blockade of this ROS-mediated redox-sensitive signal cascades may attenuate the toxic effects of MC-LR.
Insights
Microcystin-LR (MC-LR) triggers reactive oxygen species (ROS) generation, leading to p38-MAPK activation and tau hyperphosphorylation in neuroendocrine cells. Antioxidants block this pathway, suggesting ROS mediates MC-LR neurotoxicity.
Area of Science:
- Neurotoxicology
- Cellular Biology
- Environmental Health
Background:
- Microcystin-LR (MC-LR), a cyanobacterial hepatotoxin, exhibits neurotoxic effects.
- Previous studies linked MC-LR to cytoskeletal changes and protein hyperphosphorylation via PP2A inhibition and p38 MAPK activation.
- Oxidative stress from reactive oxygen species (ROS) is implicated in MC-LR toxicity, but the mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of ROS in MC-LR-induced hyperphosphorylation of tau protein and MAPK activation in PC12 cells.
- To elucidate the signaling pathways mediating MC-LR neurotoxicity.
Main Methods:
- PC12 cells were treated with MC-LR to assess time- and concentration-dependent effects on ROS generation, p38-MAPK activation, and tau phosphorylation.
- Antioxidants N-acetylcysteine and vitamin C were used as pretreatment agents.
- Western blotting and ROS detection assays were employed.
Main Results:
- MC-LR induced time- and concentration-dependent ROS generation, p38-MAPK activation, and tau hyperphosphorylation.
- ROS generation and tau hyperphosphorylation exhibited biphasic changes, peaking at 3 hours.
- Antioxidant pretreatment significantly reduced MC-LR-induced ROS, p38-MAPK activation, and tau hyperphosphorylation.
Conclusions:
- ROS generation is a critical intracellular event in MC-LR-induced p38-MAPK activation and tau phosphorylation.
- MC-LR toxicity is mediated through ROS-sensitive redox signaling cascades.
- Targeting these ROS-mediated pathways may offer a strategy to mitigate MC-LR neurotoxicity.
