An in vivo longitudinal analysis of MNs revealed that ER stress influences disease manifestations in SOD1G93A and SOD1G85R mouse models of FALS (Saxena et al., 2009). However, activation of the UPR is detrimental to mutant s-SOD1G93A mice, leading to failure to reinnervate NMJs. Conversely, treatment with salubrinal attenuated axon pathology and extended survival in mutant SOD1G93A mice (Saxena et al., 2009). Initiation of the UPR was detected specifically in FF-MNs in asymptomatic SOD1G93A mice, but not in S-MNs (Saxena et al., 2009). Hence these findings indicate that the more vulnerable MNs develop ER stress first, thus linking the UPR to MN susceptibility in ALS. FF-MNS may be more vulnerable to ER stress because they have much lower levels of BiP co-chaperone SIL1 compared to S-MNs (Filézac de L’Etang et al., 2015). SIL1 is protective against ER stress and reduces the formation of mutant SOD1 inclusions in vitro. Conversely SIL1 depletion leads to disturbed ER and nuclear envelope morphology, defective mitochondrial function, and ER stress, thus linking SIL1 to neurodegeneration (Roos et al., 2016). Furthermore, AAV-mediated overexpression of SIL1 in MNs of SOD1G93A mice preserves FF MN axons and prolongs survival by 25–30% compared to littermates (Filézac de L’Etang et al., 2015). In addition, SIL1 levels are reduced in MNs of mutant TDP-43A315T mice, and are increased in the surviving MNs of SALS patients, also implying that SIL1 is protective in ALS (Filézac de L’Etang et al., 2015).