Abstract:

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. 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, Parkinson’s disease, Alzheimer’s disease, among others. These neurodegenerative conditions are characterized by the presence of abnormal protein aggregates containing specific proteins, which are now classified as protein misfolding disorders (PMDs). The available evidence is depicting a novel scenario,
placing PDIs as interesting targets for disease intervention. Due to the fact synaptic dysfunction are salient features of most neurodegenerative conditions, the possible consequences of enforcing ERp57 expression in the brain (i.e., using gene therapy) should be explored as a strategy to improve neuronal survival, synaptic function, and enhance tissue regeneration where ERp57 could act over protein substrates involved in synaptic functions. It remains to be elucidated if other functions beyond the ER can be attributed to the beneficial effects of ERp57 expression. Of note, ERp57 has been described in subcelular localizations beyond the ER, including the nucleus, the plasma membrane and cytoplasm (Turano et al., 2002). The new mouse models generated to manipulate ERp57 levels in the nervous system represent relevant tools to assess the function of this foldase to diverse diseases. Since the PDI family of proteins
involves more than 20 members, we predict that this field will accelerate and develop toward the identification of novel functions of PDIs and other components of the ER proteostasis network on a variety of pathologies involving altered function of the secretory pathway.