title: Downregulation of Mfn2 participates in manganese-induced neuronal apoptosis in rat striatum and PC12 cells.
abstract: Manganese (Mn) is a widely distributed trace element that is essential for normal brain function and development. However, chronic exposure to excessive Mn has been known to lead to neuronal loss and manganism, a disease with debilitating motor and cognitive deficits, whose clinical syndrome resembling idiopathic Parkinson's disease (IPD). However, the precise molecular mechanism underlying Mn neurotoxicity remains largely unclear. Accumulating evidence indicates that abnormal mitochondrial functionality is an early and causal event in Mn-induced neurodegeneration and apoptosis. Here, we investigated whether Mitofusin 2 (Mfn2), a highly conserved dynamin-related protein (DRP), played a role in the regulation of Mn-induced neuronal apoptosis. We revealed that Mfn2 was significantly dysregulated in rat striatum and PC12 neuronal-like cells following Mn exposure. Western blot analysis revealed that the expression of Mfn2 was remarkably decreased following different concentrations of Mn exposure. Immunohistochemistry analysis confirmed a remarkable downregulation of Mfn2 in rat striatum after Mn exposure. Immunofluorescent staining showed that Mfn2 was expressed predominantly in neurons, and neuronal loss of Mfn2 was associated with the expression of active caspase-3 following Mn exposure. Importantly, overexpression of Mfn2 apparently attenuated Mn-induced neuronal apoptosis. Notably, treatment with caspase-3 inhibitor Ac-DEVD-CH could not rescue Mn-induced downregulation of Mfn2, suggesting that Mn-induced mfn2 occurs prior to neuronal apoptosis. Taken together, these results indicated that down-regulated expression of Mfn2 might contribute to the pathological processes underlying Mn neurotoxicity.
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China.
authors.forename: Xinhang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Public Health, The Second People's Hospital of Nantong, Nantong, Jiangsu Province, People's Republic of China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Occupational Health and Occupational Diseases, Nantong Center for Disease Control and Prevention, Nantong, Jiangsu Province, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China.
authors.forename: Shengyang
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Nie
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China.
authors.forename: Jingling
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China. Electronic address: jkjiang@ntu.edu.cn.
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D020558:GTP Phosphohydrolases; D008297:Male; D008345:Manganese / Q000633:toxicity*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D008345:Manganese; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat
keywords: Apoptosis; Manganese; Mfn2; Neurotoxicity; PC12 cells; Striatum