The current state of the field supports a pathogenic role of IRE1 pathway in ALS through activation of cell death programs, besides the possible effects of XBP1s deficiency in enhancing the activity of the autophagy pathway whereas reducing hyperexcitability in motoneurons (Nishitoh et al., 2008; Hetz et al., 2009; Kiskinis et al., 2014; Lee et al., 2016). Here, ERN1 is linked to amyotrophic lateral sclerosis.