ERp57 as a novel cellular factor controlling prion protein biosynthesis: Therapeutic potential of protein disulfide isomerases

Figures & data

FIGURE 1. ERp57, the calnexin/calreticulin cycle and PrP biosynthesis. (A) ERp57/PDIA3/Grp58 and PDIA1 are members of the Protein Disulfide Isomerase (PDI) family. The domain structure is conserved in other members of the PDI family and is indicated using color code: in blue, catalytic domains a and a’, in red and green, the non-catalytic b and b’ domains, respectively and in orange, the ER retention signal. (B) Schematic representation of the protein folding activity of ERp57, comprising the oxidation, reduction and/or the isomerization of disulfide bonds in nascent glycoproteins. (C) Schematic representations of the biosynthesis of Prion protein (PrP) through the secretory pathway (left panel), emphasizing the impact of ERp57 deficiency (right panel). Left panel: Translation of PrP is directed toward the lumen of the endoplasmic reticulum (ER), where it receives a series of post-translational modifications, including glycosylation, intramolecular disulfide bond, and a GPI anchor that targets the protein to the plasma membrane. During its passing through the ER, PrP undergoes processing and quality control, to then mature at the Golgi apparatus for its sorting to the plasma membrane. Around 10% of the newly synthesized PrP is not correctly folded, and undergoes clearance through the ER-associated degradation (ERAD) pathway. Right panel: ERp57 deficiency alters PrP biosynthesis leading to alteration in the ratio of glycosylation, accumulation of large aggregates of the protein due to cross-links by aberrant intermolecular disulfide bonds, and reduction of steady-state levels of PrP protein related to decreased half-life of the protein, which lead to altered PrP trafficking.

TABLE 1. Role of Protein Disulfide Isomerases in neurodegenerative diseases.

Disease	Effect	Reference
PrDs	• ERp57 and PDIA1 are upregulated in post mortem brain samples of CJD patients.• ERp57 levels correlate with disease progression in murine scrapie models.• ERp57 and PDIA1 expression protect against PrP^Sc toxicity in vitro.• PDIA1 is nitrosylated in PrDs models.• Inhibition of PDI activity reduces PrP^Sc replication in vitro.	^10,20,22
AD	• PDIA1 inhibits Tau aggregation.• Pharmacological activation of ERp57 reduces clinical hallmarks of AD in mouse models.• ERp57 physically interacts with amyloid-β and prevents its aggregation.• Inhibition of ERp57 and PDIA1 protects against amyloid-β toxicity.	^20,27,33
PD	• PDIA1 is upregulated in many toxicological models of PD.• PDIA1 is S-nitrosylated in brain tissue of PD patients.	^20
ALS	• ERp57 and PDIA1 mutations are risk factors to develop ALS.• PDIA1 and ERp57 are upregulated in mouse models and post mortem tissue and CSF.• Upregulation of ERp57 in blood of patients is a possible biomarker of the disease• PDIA1 reduces mutant SOD1 aggregation in vitro.• PDIA1 co-localizes with SOD1, FUS and TDP-43 inclusion in ALS-derived tissue.	^20,29,31,32
HD	• Inhibition of ERp57 or PDIA1 suppresses neuronal degeneration induced by mutant Huntingtin in vitro.	^20

A summary of selected literature related to protein disulfide isomerases in protein misfolding disorders (PMDs). Abbreviations used: PrDs, Prion related Disorders; AD, Alzheimer disease; PD, Parkinson disease; ALS, Amyotrophic Lateral Sclerosis; HD, Hungtington's disease. Most primary references can be found in.²⁰

Andreu CI, Woehlbier U, Torres M, Hetz C. Protein disulfide isomerases in neurodegeneration: From disease mechanisms to biomedical applications. FEBS Lett 2012; 586(18):2826–34; PMID:22828277; http://dx.doi.org/10.1016/j.febslet.2012.07.023

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