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.

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“…Overall, given the observed up modulation of genes known to be involved with apoptosis (Bhinge et al, 2007; Carey et al, 2013; Chen et al, 2010; Duan et al, 2013; Fedele et al, 2001; Fleischer and Rebollo, 2004; Franklin et al, 2002; Hartman et al, 2004; Jin et al, 2011; Pawlowski and Kraft, 2000; Shi et al, 2015; Thyss et al, 2005), and concurrent up modulation of genes involved with fatty acid biosynthesis, ribosome biogenesis, and the cellular stress response, one shared primary response for both females and males is to arrest the cell cycle. This is consistent with the concept of UVB damaged cells to either repair DNA damage caused by UVB exposure or induce apoptosis in cells containing extensive DNA damage at the higher dose (e.g.…”

Manganese Is Essential for Neuronal Health

“…Increased levels of p53 have been found in cortical neurons and glial cells from Mn-exposed nonhuman primates, and analysis of gene expression changes in cortical tissue from these Mn-exposed animals has revealed a prominent role of p53 in Mn-induced alterations in gene expression (117, 118). K-homology splicing regulator protein, a regulatory protein involved in neuronal apoptotic signaling, is upregulated in Mn-exposed striatum along with p53, providing further evidence of the role of p53 in Mn neurotoxicity (257). Recently, a major p53 response to Mn exposure was found in mouse striatal cells and human neuroprogenitors.…”

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

“…Mn exposure (300 μM Mn for 6–24) was also shown to depress p73 mRNA expression in an N27 dopaminergic neuronal model thus increasing susceptibility of neuronal cells to apoptosis [ 141 ]. Mn-induced apoptosis may be at least partially dependent on K-homology splicing regulator protein (KHSRP) up-regulation that was found to be overexpressed in association with proapoptotic genes and colocalized with active caspase-3 in PC12 cells exposed to Mn (0–1000 μM for 1–24 h) [ 142 ].…”