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

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Journal of Inherited Metabolic Disease

Abstract

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.

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Acknowledgments

The fibroblasts used in this study and their genotypes were obtained from the “Cell Line and DNA Biobank from Patients Affected by Genetic Diseases”– Telethon Genetic Biobank Network (Project No. GTB07001A). This study was supported by the following grants to Prof. P. Di Natale: 1) Telethon grant 2007 n. GGP07043; 2) Grant from MIUR-Italy; 3) Associazione Italiana Mucopolisaccaridosi e Malattie Affini (Milan, Italy).

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  1. Department of Biochemistry and Medical Biotechnologies, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy

    Guglielmo R. D. Villani, Armando Chierchia & Paola Di Natale

  2. Center for Animal Experimentation, Cardarelli Hospital, 80128, Naples, Italy

    Daniele Di Napoli

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  1. Guglielmo R. D. Villani
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  2. Armando Chierchia
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  3. Daniele Di Napoli
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Correspondence to Guglielmo R. D. Villani.

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Communicated by: Eva Morava

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Villani, G.R.D., Chierchia, A., Di Napoli, D. et al. Unfolded protein response is not activated in the mucopolysaccharidoses but protein disulfide isomerase 5 is deregulated. J Inherit Metab Dis 35, 479–493 (2012). https://doi.org/10.1007/s10545-011-9403-8

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