Involvement of MEK5/ERK5 signaling pathway in manganese-induced cell injury in dopaminergic MN9D cells |
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| Affiliation: | 1. School of Public Health, Zunyi Medical University, Zunyi, Guizhou, PR China;2. School of Health Sciences, Purdue University, West Lafayette, Indiana, USA;3. The First Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, PR China;1. Department of Pediatrics, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan;2. Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan;3. Department of Neurosurgery, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan;4. Research Fellow of Japan Society for the Promotion of Science, Japan;1. University of Potsdam, Institute of Nutritional Science, Department of Food Chemistry, Arthur-Scheunert-Allee 114-116, Nuthetal, Germany;2. University of Graz, Institute of Chemistry, NAWI Graz, Universitaetsplatz 1, Graz, Austria;3. University of Würzburg, Institute of Pharmacology and Toxicology, Department of Toxicology, Versbacher Str. 9, Würzburg, Germany;1. School of Health Sciences, Purdue University, West Lafayette, IN, USA;2. School of Public Health, Qingdao University, Qingdao, China;3. Departments of Physiology, Qingdao University Medical College, Qingdao, China;4. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA;1. Department of Environment and Health, Italian National Institute for Health, Viale Regina Elena 299, 00161 Rome, Italy;2. Department of Biomedical Sciences—Histology, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy;3. Department of Medical Surgical and Experimental Sciences, Ophthalmology Unit, University of Sassari, Viale San Pietro 43/C, 07100 Sassari, Italy;4. I.S.R.C.T.––International Society for Research on Cadmium Toxicity, Viale San Pietro 43/B, 07100 Sassari, Italy;1. Department of Family Planning Technical Service, Jining Maternal and Child Health Family Planning Service Center, No.12, Gongxiao Road, Rencheng District, Jining City, Shandong Province, 272000, China;2. Department of Laboratory, Jining Maternal and Child Health Family Planning Service Center, No.12, Gongxiao Road, Rencheng District, Jining City, Shandong Province, 272000, China |
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| Abstract: | BackgroundOver-exposure to manganese (Mn) causes irreversible movement disorders with signs and symptoms similar, but not identical, to idiopathic Parkinson's disease (IPD). Recent data suggest that Mn toxicity occurs in dopaminergic (DA) neurons, although the mechanism remains elusive. This study was designed to investigate whether Mn interfered the apoptotic signaling transduction cascade in DA neurons.MethodsMouse midbrain dopaminergic MN9D cells were exposed to Mn in a concentration range of 0, 400, 800, or 1200 μM as designated as control, low, medium, and high exposure groups, respectively. The flow cytometry with Annexin V/PI double staining and immunohistochemistry were used to assess the apoptosis.ResultsData indicated that Mn exposure caused morphological alterations typical of apoptosis, increased apoptotic cells by 2–8 fold, and produced reactive oxidative species (ROS) by 1.5–2.2 fold as compared to controls (p < 0.05). Studies by qPCR and Western blot revealed that Mn exposure significantly increased the protein expression of extracellular signal-regulated kinase-5 (ERK5) and mitogen-activated ERK kinase-5 (MEK5) (p < 0.05). The presence of BIX02189, a specific inhibitor of MER/ERK, caused a much greater cytotoxicity, i.e., higher cell death, more ROS production, and worsened apoptosis, than did the treatment with Mn alone. Following Mn exposure, the expression of a downstream effector Bcl- 2 was reduced by 48 % while those of Bax and Caspase-3 were increased by 266.7 % and 90.1 %, respectively, as compared to controls (p < 0.05).ConclusionTaken together, these data provide the initial evidence that the signaling transduction cascade mediated by MEK5/ERK5 is responsible to Mn-induced cytotoxicity; Mn exposure, by suppressing anti-apoptotic function while facilitating pro-apoptotic activities, alters neuronal cell’s survival and functionally inhibits DA production by MN9D cells. |
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| Keywords: | Manganese MEK5/ERK5 MN9D Apoptosis Bcl-2 Bax |
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