title: KHSRP participates in manganese-induced neurotoxicity in rat striatum and PC12 cells.
abstract: Manganese (Mn) is an essential micronutrient. However, exposure to high doses of Mn may lead to a neurological disease known as manganism, which is characterized by marked brain neuronal loss. K-homology splicing regulator protein (KHSRP) is a multifunctional RNA-binding protein and has been implicated in the regulation of multiple cellular signaling associated with neuronal apoptosis and survival, such as p38 mitogen-activated protein kinase (MAPK), nuclear factor kappaB (NF-κB), and Wnt/β-catenin pathways. In the present study, the role of KHSRP in Mn-induced neurotoxicity was investigated in vivo using a rat model of chronic Mn exposure and in vitro using differentiated PC12 cell cultures. Western blot and immunohistochemical analyses showed a significant upregulation of KHSRP in rat striatum following Mn exposure. Immunofluorescent labeling indicated that KHSRP was localized mainly in neurons. Terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick end labeling (TUNEL) assay showed that KHSRP was mainly distributed in apoptotic neurons. Increased KHSRP expression was positively correlated with the upregulation of several apoptosis-related proteins, such as p53, bax, and active caspase-3. In addition, significant co-localization of KHSRP and active caspase-3 in neurons after Mn exposure was also observed, suggesting a potential involvement of KHSRP in the regulation of Mn-induced striatal neuronal apoptosis. Importantly, interference with KHSRP apparently decreased the level of p53 and attenuated Mn-induced neuronal apoptosis. Taken together, these results indicate that upregulation of KHSRP may be involved in the pathological process underlying Mn neurotoxicity via the modulation of p53 signaling.
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: Shangshi
authors.initials: S
authors.lastname: Shi
authors.forename: Jianya
authors.initials: J
authors.lastname: Zhao
authors.forename: Lingling
authors.initials: L
authors.lastname: Yang
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Nie
authors.forename: Jingling
authors.initials: J
authors.lastname: Han
authors.forename: Xia
authors.initials: X
authors.lastname: Ma
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008345:Manganese / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C000601121:KHSRP protein, rat; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D008345:Manganese