Abstract
BackgroundProtein disulfide isomerase (PDI), is sorted to be enzymatic chaperone for reconstructing misfolded protein in endoplasmic reticulum lumen. Recently, PDI has been identified as a link between misfolded protein and neuron apoptosis. However, the potential for PDI to be involved in the pathogenesis of prion disease remains unknown. In this study, we propose that PDI may function as a pleiotropic regulator in the cytotoxicity induced by mutated prion proteins and in the pathogenesis of prion diseases.Methodology/Principal FindingsTo elucidate potential alterations of PDI in prion diseases, the levels of PDI and relevant apoptotic executors in 263K infected hamsters brain tissues were evaluated with the use of Western blots. Abnormal upregulation of PDI, Grp78 and Grp58 was detected. Dynamic assays of PDI alteration identified that the upregulation of PDI started at the early stage and persistently increased till later stage. Obvious increases of PDI and Grp78 levels were also observed in cultured cells transiently expressing PrP mutants, PrP-KDEL or PrP-PG15, accompanied by significant cytotoxicities. Excessive expression of PDI partially eased ER stress and cell apoptosis caused by accumulation of PrP-KDEL, but had less effect on cytotoxicity induced by PrP-PG15. Knockdown of endogenous PDI significantly amended cytotoxicity of PrP-PG15, but had little influence on that of PrP-KDEL. A series of membrane potential assays found that apoptosis induced by misfolded PrP proteins could be regulated by PDI via mitochondrial dysfunction. Moreover, biotin-switch assays demonstrated active S-nitrosylted modifications of PDI (SNO-PDI) both in the brains of scrapie-infected rodents and in the cells with misfolded PrP proteins.Conclusion/SignificanceCurrent data in this study highlight that PDI and its relevant executors may function as a pleiotropic regulator in the processes of different misfolded PrP proteins and at different stages during prion infection. SNO-PDI may feed as an accomplice for PDI apoptosis.
Highlights
Prion disorders, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases affecting humans and many species of animals, for example Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and goat, and bovine spongiform encephalopathy (BSE) in cattle
The real function of prion protein is still unknown, it is obvious that deposits of pathogenic or misfolded prion proteins could result in neuronal damage during the pathogenesis of prion diseases [22]
Time-course studies revealed that Protein disulfide isomerase (PDI) in the brains of infectious prion experimental animals is upregulated as the disease progression
Summary
Transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases affecting humans and many species of animals, for example Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and goat, and bovine spongiform encephalopathy (BSE) in cattle. The mechanism of PrPSc pathogenesis is still controversial, mounting evidences suggests that perturbations in endoplasmic reticulum (ER) homeostasis or mitochondrial dysfunction induced by PrPSc or misfolded prion proteins may contribute to cell death or neurodegenerative pathology in prion disease [2,3,4]. When ER homeostasis is perturbed, ER stress triggers the survival pathway, unfolding protein response (UPR), which is associated with upregulation of ER-derived chaperones and protein-folding enzymes leading the misfolded proteins undergoing the process of degeneration [5,6]. It was revealed that PDI and Grp were involved in apoptosis induced by misfolded proteins [10]. We propose that PDI may function as a pleiotropic regulator in the cytotoxicity induced by mutated prion proteins and in the pathogenesis of prion diseases
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