Unfolded protein response is not activated in the mucopolysaccharidoses but protein disulfide isomerase 5 is deregulated.

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases (LSDs) caused by defects in lysosomal enzymes involved in the catabolism of glycosaminoglycans. The pathogenesis of these disorders is still not completely known, although inflammation and oxidative stress appear to be common mechanisms, as in all LSDs. Recently, it was hypothesized that endoplasmic reticulum (ER) stress followed by an unfolded protein response (UPR) could be another common pathogenetic mechanism in LSDs. The aim of the present study was to verify if the UPR was elicited in the mucopolysaccharidoses and if the mechanism was MPS type- and mutation-dependent. To this end, we analyzed the UPR in vitro, in fibroblasts from patients with different types of mucopolysaccharidoses (MPS I, II, IIIA, IIIB, IVA) and in vivo, in the murine MPS IIIB model. In both cases we found no changes in mRNA levels of several UPR-related genes, such as the spliced or unspliced form of Xbp-1, Bip, Chop, Edem1, Edem2, Edem3. Therefore, we report here that the unfolded protein response of the ER is not triggered either in vitro or in vivo; accordingly, cytotoxicity assays indicated that affected fibroblasts are no more sensitive to apoptosis induction than normal cells. However, our results show that in most of the analyzed MPS fibroblasts the expression of a poorly known protein belonging to the family of the protein disulfide isomerases, namely Pdia5, is upregulated; here we discuss if its upregulation could be an early event of ER stress possibly related to the severity of the damage induced in the mutant proteins.