PDI is also upregulated in SOD1 mice and human SALS spinal cord tissues (Ilieva et al., 2007; Atkin et al., 2008; Sasaki, 2010; Walker et al., 2010; Chen et al., 2015; Sun et al., 2015). Wild type PDI overexpression and related family member Erp57 are protective in vitro in neuronal cells expressing mutant SOD1 (Walker et al., 2010; Jeon et al., 2014; Parakh et al., 2018a). Interestingly, mutations in PDI and Erp57 have been identified in ALS patients, and expression in zebrafish induces motor defects (Woehlbier et al., 2016). Furthermore, the levels of PDI in MNs are lower than in astrocytes and oligodendrocytes in SOD1G37R mice (Sun et al., 2015). This implies that MNs are intrinsically more vulnerable to unfolded protein accumulation than other cell types, which may also contribute to their susceptibility in ALS.