title: Upregulation of mitochondrial protease HtrA2/Omi contributes to manganese-induced neuronal apoptosis in rat brain striatum.
abstract: Manganese (Mn) is an essential trace element that is required for normal brain functioning. However, excessive intake of Mn has been known to lead to neuronal loss and clinical symptoms resembling idiopathic Parkinson's disease (IPD), whose precise molecular mechanism remains largely elusive. In the study, we established a Mn-exposed rat model and identified a mitochondrial protease, the mature form of high temperature requirement A2 (HtrA2/Omi), which was significantly upregulated in rat brain striatum after Mn exposure. Western blot and immunohistochemical analyses revealed that the expression of mature HtrA2 was remarkably increased following Mn exposure. In addition, immunofluorescence assay demonstrated that overexposure to Mn could lead to significant elevation in the number of HtrA2-positive neurons. Accordingly, the expression of X-linked inhibitor of apoptosis protein (XIAP), a well-characterized target of HtrA2-mediated proteolysis, was progressively decreased following Mn exposure, and was correlated with increased level of active caspase-3. Further, we showed that Mn exposure decreased the viability and induced apparent apoptosis of NFG-differentiated PC12 cells. Importantly, the expression of HtrA2 was progressively increased, whereas the level of cellular XIAP was reduced during Mn-induced apoptosis. In addition, blockage of HtrA2 activity with UCF-101 restored Mn-induced reduction in XIAP expression. Finally, we observed that UCF-101 treatment ameliorated Mn-induced apoptosis in PC12 cells. Collectively, these findings suggested that upregulated HtrA2 played a role in Mn-induced neuronal death in brain striatum.
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors.forename: J K
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.affiliation: The Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China.
authors.forename: Q Y
authors.initials: QY
authors.lastname: Wu
authors.affiliation: Medical Image 103, Medical College, Nantong University, Nantong, People's Republic of China.
authors.forename: W B
authors.initials: WB
authors.lastname: Qian
authors.affiliation: The Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China.
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors.forename: S S
authors.initials: SS
authors.lastname: Shi
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors.forename: J L
authors.initials: JL
authors.lastname: Han
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors.forename: J Y
authors.initials: JY
authors.lastname: Zhao
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors.forename: S Y
authors.initials: SY
authors.lastname: Jiang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, People's Republic of China. Electronic address: Chwan@ntu.edu.cn.
authors.forename: C H
authors.initials: CH
authors.lastname: Wan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D011744:Pyrimidinones / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068103:Serine-Arginine Splicing Factors; D013871:Thiones / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D009419:Nerve Tissue Proteins; D011744:Pyrimidinones; D016601:RNA-Binding Proteins; D013871:Thiones; C490770:Tra2b protein, rat; C501517:UCF 101; C494837:Xiap protein, rat; D000068103:Serine-Arginine Splicing Factors; D008345:Manganese; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: HtrA2/Omi; XIAP; apoptosis; manganese; neurotoxicity; striatum