ER stress. A cell’s survival is closely connected to its ability to control for the quality of its proteins. Protein folding in vivo is a very inefficient process and so cells have evolved a complex interconnected regulatory network which aids in balancing the strain of protein biosynthesis, protein folding and protein degradation (Xxxx and Xxxxxx, 2010; Xxxxx et al., 2011; Xxxxxx and Xxxxxx, 2011). These homeostatic mechanisms help cells to cope with altered physiological conditions, to survive periods of acute stress and to adapt to milder but chronic stress conditions (Xxxxxx and Xxxxxx, 2011). However, accumulations of unfolded or misfolded proteins are still possible even if the regulatory networks are functioning normally. Accumulations of this sort are possible due to translational or transcriptional errors, genetic mutations, toxic reagents or other cellular stresses (Xxxxxx and Xxxxxxx, 2008; Xxxxx et al., 2011). Degradation systems in a cell include ER-associated protein degradation (ERAD), the endo- lysosomal pathway, the ubiquitin proteasome system and autophagy (Vembar and Xxxxxxx, 2008). All of these systems have specific stress sensors that enable the cell to rapidly respond to disturbances in protein homeostasis (Xxxxxxxx et al., 2006). One of the response mechanisms is the unfolded protein response (UPR) which responds to an accumulation of unfolded proteins in the ER (Xxxxxxxx et al., 2006; Xxxxxxxx et al., 2009). The UPR restores proteostasis by a) attenuating translation to alleviate the protein load of the ER, b) inducing the transcription of chaperones to aid protein folding and c) upregulating degradation pathways (ERAD, autophagy) (Xxxxxxxx et al., 2009). Chronic ER stress can lead to apoptosis (Xxxxxxxx et al., 2000; Xxxxxxxx et al., 2002). Since this thesis involves work concerning the UPR, this aspect will be covered in more detail in section 1.5. Morphological changes of the ER and the Golgi apparatus indicate a general dysfunction of the ER-secretory pathway and protein degradation pathways in ALS (Xxxxxxxxx et al., 2012). Mutant SOD1 transgenic mice show a dilatation of the ER and a detachment of ribosomes from the ER surface in pre- and early- symptomatic stages of the disease (Xxx Xxxxx and Xxxxxx, 1997). Fragmentation of the ER, abnormal distention of the ER cisternae, ribosomal detachment and granular accumulation of material in the ER lumen has been found in post-mortem samples of ALS spinal cord tissue (Oyanagi et al., 2008; Xxxxxx...
