The protein disulfide isomerases (PDIs) family has a central function in the folding of proteins synthetized through the secretory pathway. ERp57, also known as Grp58 or PDIA3, is one of the main studied members of this family. ERp57 catalyzes the formation, disruption and isomerization of disulfide bonds of glycoproteins mediated by a cooperative interaction with the endoplasmic reticulum (ER) chaperones calnexin and calreticulin (Turano et al., 2002) [Figure 1]A, B). In the past years, several studies have linked ERp57 and its closest homologue PDI (also known as PDIA1) to diseases affecting the central nervous system, including amyotrophic lateral sclerosis (ALS), Parkinsons disease (PD), Alzheimers disease (AD), among others (Andreu et al., 2012). These neurodegenerative conditions are characterized by the presence of abnormal protein aggregates containing specific proteins, which are now classified as protein misfolding disorders (PMDs) (Hetz and Mollereau, 2014).