In conclusion we demonstrate that infection of salmon

In conclusion we demonstrate that infection of salmon cells with ISAV induce the main branches of the cellular UPR machinery, but also one of its main negative regulators, GADD34. This is probably important for maintaining translation of interferon and interferon stimulated genes (ISGs), keeping ISAV replication at a low level compared to other piscine RNA viruses (Gomez-Casado et al., 2011).
Acknowledgments This work was funded by grant# 190625 from MLS@UiO.
Introduction Manganese (Mn) is an essential metal found in a variety of biological tissues and is necessary for normal functioning of a variety of physiological processes including amino acid, lipid, protein and carbohydrate metabolism. Despite its essentiality, Mn has been known to be a neurotoxicant. Elevated occupational exposure to Mn posed a health risk (Roels et al., 2012). Elevated Nevirapine synthesis Mn concentrations were associated with occupational exposure to high levels of inhaled Mn such as in ferroalloy smelting, welding, mining, battery assembly and the manufacture of glass ceramics (Criswell et al., 2012). Mn exposure had also focused on the use of a Mn-containing fuel additive, methylcyclopentadienyl Mn tricarbonyl (MMT), as an anti-knock agent in gasoline in Canada and other Western nations (Boudia et al., 2006). Mn neurotoxicity was first identified as a dystonic neurodegenerative movement disorder that resulted from excessive accumulation of Mn within the basal ganglia and presented with neurologic symptoms resembling features of Parkinson\'s disease. Epidemiological studies have suggested a causal relationship between elevated environmental Mn exposure and increased risk for Parkinsonian-like symptoms (Guilarte, 2010). Several mechanisms of Mn-induced neurotoxicity had been proposed, including mitochondrial dysfunction, aberrant signal transduction, oxidative stress and the activation of cell death pathways etc. (Milatovic et al., 2009). The mechanisms underlying the neurotoxicity of Mn are still incompletely understood but seem to involve endoplasmic reticulum (ER) stress (Matus et al., 2012). Yoon et al. (2011a) found that Mn-induced apoptosis might involve in two intrinsic pathways, ER stress and mitochondria dysfunction. The ER stress has been known to play a role in many neurodegenerative diseases as well as other diseases. It is caused from the accumulation of excessive unfold protein response (UPR) which leads to cell apoptosis. The ER is an organelle that is important for the synthesis, correct folding, posttranslational modification, and transport of nascent proteins. The presence of a protein overload in the ER that exceeds its folding capacity results in ER stress. In the course of ER stress, signaling pathways that act to protect cells against the toxic buildup of misfolded protein, including the UPR, are activated (Lind et al., 2013). The UPR is initiated when the unfolded proteins exceed the capacity of chaperone proteins, such as 78, 94-kDa glucose-regulated protein (GRP78, 94), which normally binds to the C-terminal ends of three trans-membrane proteins; pancreatic ER kinase RNA (PKR) like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) in an inactive form. The pro-apoptotic protein C/EBP homologous protein (CHOP) and cleaved caspase-12 are characteristically responsive to ER stress (Roussel et al., 2013). Although several studies have reported that Mn could induce ER stress (Chun et al., 2001, Yoon et al., 2011a), little data in detail exist on the effects of Mn on the three UPR signal pathways, information that is critical for more fully evaluating the Mn-induced neurotoxicity. Therefore, to explore the relationship between the ER stress and the Mn-induced neurotoxicity, we used in vitro cultured brain slices model and found that Mn induced ER stress via the PERK and IRE1 signal pathways.
Materials and methods
Results
Discussion Neural injury was assessed by the release of LDH and apoptosis assays. In this study, the treatment with Mn resulted in a time-dependent increase in the percentage of early apoptotic cells and levels of LDH in the culture medium. These results indicated that Mn treatment caused appreciable neurotoxicity as reported previously (Yoon et al., 2011a). According to previously reported (Chun et al., 2001, Yoon et al., 2011a), we considered the mechanism of Mn-induced neurotoxicity was related to ER stress, which was supported by our data.