Initial studies using mutant SOD1 mice demonstrated that the PERK-UPRER acts protectively in ALS pathogenesis (Wang et al., 2011, 2014a), though a more recent study using several strains of mutant SOD1 mice demonstrated that manipulating the PERK pathway had no effect on disease onset or progression, which could reflect relative differences in mutant SOD1 expression levels between mice strains (Dzhashiashvili et al., 2019). This evidence concerns the gene EIF2AK3 and amyotrophic lateral sclerosis.