title: Microcystin-LR induces cytoskeleton system reorganization through hyperphosphorylation of tau and HSP27 via PP2A inhibition and subsequent activation of the p38 MAPK signaling pathway in neuroendocrine (PC12) cells.
abstract: Cyanobacteria-derived microcystin-LR (MC-LR) commonly characterized as a hepatotoxin has recently been documented to show potential neurotoxicity, but the detailed neurotoxic effects of MC-LR and its mechanisms are unclear. In the present study, the neuroendocrine PC12 cell line was used to investigate whether MC-LR causes alterations of neuronal morphology and abnormalities in the phosphorylation status of cytoskeletal-associated proteins, and to elucidate the underlying mechanisms. The results showed that treatment of PC12 cells with MC-LR-triggered microtubule (MT) and actin cytoskeleton rearrangement, leading to a loss of their filamentous distribution and the display of a similar rearrangement pattern with decreased amounts of tubules or actin fibers in the cytosol and increased amounts of these structures in the cell periphery. An increase in MT tyrosination and a decrease in MT acetylation, which demonstrated MT destabilization, were also found. Moreover, MC-LR-induced hyperphosphorylation of the neural microtubule-associated protein tau, which correlated with an increase in soluble tau and a decrease in cytoskeleton-associated tau. Besides, the phosphorylation of the actin-associated protein HSP27 was also increased in MC-LR-treated cells. Furthermore, MC-LR caused a concentration-dependent decrease in the activity of protein phosphatase 2A (PP2A), and a dramatic activation of p38 mitogen-activated protein kinase (MAPK). The dephosphorylated tau dissociated from PP2A, whereas the tau phosphorylation status paralleled the activation of p38 MAPK. Pretreatment with the p38 MAPK inhibitor SB203580 effectively abolished hyperphosphorylation of tau and HSP27, and blocked MC-LR-triggered cytoskeletal alterations. Taken together, MC-LR leads to the reorganization of cytoskeletal architectures in PC12 cells and hyperphosphorylation of tau and HSP27, which may be caused by direct PP2A inhibition and indirect p38 MAPK activation.
authors: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, 866th Yu Hang Tang Road, Hangzhou 310058, China.
authors: Guanmin
authors: G
authors: Meng
authors: Yu
authors: Y
authors: Sun
authors: Wenyu
authors: W
authors: Fu
authors: Zonglou
authors: Z
authors: Guo
authors: Lihong
authors: L
authors: Xu
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055551:HSP27 Heat-Shock Proteins / Q000187:drug effects* / Q000378:metabolism; D008387:Marine Toxins; D052998:Microcystins / Q000008:administration & dosage / Q000633:toxicity*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000199:Actins; D055551:HSP27 Heat-Shock Proteins; D008387:Marine Toxins; D052998:Microcystins; D016875:tau Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; C057862:cyanoginosin LR