title: Pivotal roles of p53 transcription-dependent and -independent pathways in manganese-induced mitochondrial dysfunction and neuronal apoptosis.
abstract: Chronic exposure to excessive manganese (Mn) has been known to lead to neuronal loss and a clinical syndrome resembling idiopathic Parkinson's disease (IPD). p53 plays an integral role in the development of various human diseases, including neurodegenerative disorders. However, the role of p53 in Mn-induced neuronal apoptosis and neurological deficits remains obscure. In the present study, we showed that p53 was critically involved in Mn-induced neuronal apoptosis in rat striatum through both transcription-dependent and -independent mechanisms. Western blot and immunohistochemistrical analyses revealed that p53 was remarkably upregulated in the striatum of rats following Mn exposure. Coincidentally, increased level of cleaved PARP, a hallmark of apoptosis, was observed. Furthermore, using nerve growth factor (NGF)-differentiated PC12 cells as a neuronal cell model, we showed that Mn exposure decreased cell viability and induced apparent apoptosis. Importantly, p53 was progressively upregulated, and accumulated in both the nucleus and the cytoplasm. The cytoplasmic p53 had a remarkable distribution in mitochondria, suggesting an involvement of p53 mitochondrial translocation in Mn-induced neuronal apoptosis. In addition, Mn-induced impairment of mitochondrial membrane potential (ΔΨm) could be partially rescued by pretreatment with inhibitors of p53 transcriptional activity and p53 mitochondrial translocation, Pifithrin-α (PFT-α) and Pifithrin-μ (PFT-μ), respectively. Moreover, blockage of p53 activities with PFT-α and PFT-μ significantly attenuated Mn-induced reactive oxidative stress (ROS) generation and mitochondrial H₂O₂ production. Finally, we observed that pretreatment with PFT-α and PFT-μ ameliorated Mn-induced apoptosis in PC12 cells. Collectively, these findings implicate that p53 transcription-dependent and -independent pathways may play crucial roles in the regulation of Mn-induced neuronal death.
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226019 Jiangsu, PR China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR China.
authors.forename: Xa
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR China.
authors.forename: Shangshi
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR China.
authors.forename: Jianya
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR 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 226019 Jiangsu, PR 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 226019 Jiangsu, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226019 Jiangsu, PR China.
authors.forename: Shengyang
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019 Jiangsu, PR China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226019 Jiangsu, PR China. Electronic address: Jiang_junkang@163.com.
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology / Q000627:therapeutic use; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008345:Manganese / Q000737:chemistry / Q000633:toxicity; D020149:Manganese Poisoning / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D021381:Protein Transport / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C545747:2-phenylacetylenesulfonamide; D000931:Antidotes; D052160:Benzothiazoles; D009419:Nerve Tissue Proteins; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D008345:Manganese; C121565:pifithrin
keywords: Apoptosis; Manganese; Neurotoxicity; Striatum; p53