The ER is responsible for the folding and quality control of virtually all proteins that transit through the secretory pathway. Hence it is a fundamental aspect of proteostasis. Unfolded or misfolded proteins are retained in the ER, which activates the unfolded protein response (UPR). This aims to improve the cellular protein folding capacity by inhibiting translation, upregulating ER chaperones – such as immunoglobulin binding protein (BiP) and protein disulfide isomerase (PDI) – and stimulating protein degradation (Walter and Ron, 2011; Rozas et al., 2017; Shahheydari et al., 2017). Numerous ALS-related proteins chronically active the UPR, including ALS-associated mutant forms of SOD1 (Nishitoh et al., 2008), TDP-43 (Walker et al., 2013), C9orf72 (Dafinca et al., 2016), Vesicle-associated membrane protein-associated protein B (VAPB) (Suzuki et al., 2009) and FUS (Farg et al., 2012). ER stress has also been detected in sporadic ALS patients (Ilieva et al., 2007; Atkin et al., 2008). Furthermore, ER stress is linked to excitability in ALS. Mutant SOD1 induces a transcriptional signature characteristic of ER stress, which also disrupts MN excitability (Kiskinis et al., 2014). Similarly, modulating the excitability properties of human iPSC-derived MNs alters the UPR (Kiskinis et al., 2014). Conversely, treatment of MNs with salubrinal, an inhibitor of ER stress which inhibits eIF2α dephosphorylation (Boyce et al., 2005), reduced the excitability of MNs (Kiskinis et al., 2014). Similar results were obtained in MNs from patients carrying C9orf72 repeat expansions or VCP mutations (Kiskinis et al., 2014; Dafinca et al., 2016; Hall et al., 2017). Moreover, pharmacological reduction of neuronal excitability in SOD1G93A mice specifically reduced BiP accumulation in ipsilateral FALS α-MNs (Saxena et al., 2013). Hence, together these findings indicate that induction of the UPR and the electrical activity of MNs are both closely related in ALS.