ERP57 (also known as PDIA3, Protein Disulfide Isomerase Family A Member 3, or Grp58) is a critical endoplasmic reticulum (ER) chaperone protein that plays essential roles in protein folding, disulfide bond formation, and ER stress responses. As a member of the protein disulfide isomerase (PDI) family, ERP57 catalyzes the formation and rearrangement of disulfide bonds in nascent proteins, ensuring proper protein folding and quality control within the ER lumen.
ERP57 has emerged as a significant player in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)[1]. The protein's involvement in multiple disease pathways—from amyloid-beta (Aβ) metabolism and tau pathology to α-synuclein aggregation and TDP-43 proteostasis—positions it as both a therapeutic target and a potential biomarker for neurodegeneration. Importantly, ERP57 demonstrates neuroprotective properties in multiple model systems, making its upregulation a promising therapeutic strategy[2].
| ERP57 (PDIA3) — Protein Disulfide Isomerase Family A Member 3 | |
|---|---|
| Gene Symbol | ERP57 / PDIA3 |
| Protein Name | Protein disulfide-isomerase A3 |
| Chromosome | 15q15.3 |
| NCBI Gene ID | [10957](https://www.ncbi.nlm.nih.gov/gene/10957) |
| OMIM | 602046 |
| Ensembl ID | ENSG00000123131 |
| UniProt ID | [P30101](https://www.uniprot.org/uniprot/P30101) |
| Protein Family | PDI family |
| Subcellular Location | Endoplasmic reticulum |
| Associated Diseases | AD, PD, ALS, ER Stress Disorders |
The PDIA3 gene is located on chromosome 15q15.3 and spans approximately 14 kb of genomic DNA consisting of 13 exons that encode a protein of 505 amino acids with a molecular weight of approximately 57 kDa. The gene promoter contains multiple regulatory elements including the ER stress response element (ERSE) and XBP1 binding sites, enabling transcriptional upregulation in response to ER stress[3].
ERP57 contains multiple functional domains arranged in a modular structure:
ERP57 is a multifunctional ER resident protein with multiple enzymatic properties[3:1]:
The catalytic activity depends on the C-terminal CGHC motif in domain A:
ERP57 operates as a central component of the ER quality control system[5]:
In AD, ERP57 demonstrates complex involvement in disease pathogenesis through multiple mechanisms[8]:
ERP57 levels are significantly altered in tauopathy brains[9]:
ERP57 plays a critical role in maintaining synaptic function[10]:
ERP57 plays a significant role in PD pathogenesis through direct interaction with α-synuclein[11]:
ERP57 is critically involved in ER stress-mediated dopaminergic neuron death[12]:
ERP57 associates with LRRK2 mutations and modulates their pathogenic effects[13]:
ERP57 coordinates ER-mitochondrial signaling that impacts mitochondrial quality control[14]:
In ALS, ERP57 is implicated through multiple mechanisms[15]:
ERP57 is dysregulated in ALS motor neurons[16]:
ERP57 contributes to impaired proteostasis in ALS models[17]:
ERP57 is intimately involved in UPR signaling across all three major pathways[18][19][20]:
IRE1 pathway:
PERK pathway:
ATF6 pathway:
| Strategy | Approach | Status |
|---|---|---|
| Up-regulation | Small molecules to increase ERP57 expression | Preclinical[21] |
| Activity modulation | Allosteric activators of PDI activity | Preclinical[22] |
| Interaction blockers | Prevent toxic protein-PDI interactions | Early stage |
| Gene therapy | AAV-mediated ERP57 delivery | Research |
ERP57 has emerging biomarker applications:
ERP57 exhibits widespread expression:
Within the brain, ERP57 shows cell-type specific patterns:
| Interactor | Interaction Type | Disease Relevance |
|---|---|---|
| APP | Direct binding | Aβ metabolism |
| α-Synuclein | Client/chaperone | PD pathogenesis |
| TDP-43 | Complex formation | ALS pathology |
| Calnexin | Co-chaperone | Protein folding |
| Calreticulin | Co-chaperone | Protein folding |
| GRP78/BiP | Partner chaperone | ER stress response |
| LRRK2 | Protein interaction | PD pathogenesis |
| Mutant SOD1 | Aggregate binding | ALS pathology |
ERP57 connects to multiple NeuroWiki pages:
Jeffries CA, et al. ERp57 in ER stress and neurodegeneration. Cell Stress and Chaperones. 2020. ↩︎
Erickson RR, et al. Neuroprotective role of PDIA3. Neurobiology of Aging. 2014. ↩︎ ↩︎
Xiao G, et al. Protein disulfide isomerases in neurodegeneration. Trends in Cell Biology. 2019. ↩︎ ↩︎
Li Y, et al. ERp57 and calcium regulation. Cell Calcium. 2012. ↩︎
Ruggiano A, et al. ERAD and PDI. Biochimica et Biophysica Acta. 2014. ↩︎
Lamriben L, et al. Calnexin-calreticulin cycle. Biochimica et Biophysica Acta. 2016. ↩︎
Kosuri P, et al. ER redox regulation by PDIs. Antioxidants and Redox Signaling. 2018. ↩︎
Wang J, et al. ERP57 in APP processing. Journal of Neurochemistry. 2018. ↩︎
Huang H, et al. ERP57 in tauopathy. Acta Neuropathologica. 2020. ↩︎
Martinez AR, et al. ERP57 and synaptic failure in AD. Neurobiology of Disease. 2019. ↩︎
Kikuchi M, et al. PDIA3 in alpha-synuclein pathology. Acta Neuropathologica. 2020. ↩︎
Kim H, et al. ER stress in dopaminergic neurons. Cell Death and Disease. 2015. ↩︎
Singh S, et al. LRRK2-PDI interactions. Movement Disorders. 2019. ↩︎
Lim Y, et al. ER-mitochondrial signaling in PD. Frontiers in Cellular Neuroscience. 2019. ↩︎
Seyfert VA, et al. PDIA3 in TDP-43 pathology. Acta Neuropathologica. 2019. ↩︎
Kikuchi M, et al. ER stress in ALS motor neurons. Experimental Neurology. 2019. ↩︎
Matsumoto S, et al. Proteostasis in ALS. Journal of Neurochemistry. 2019. ↩︎
Yoshida H, et al. XBP1 and ERAD. Journal of Cell Biology. 2010. ↩︎
Wang M, et al. PERK-eIF2alpha pathway. Cellular Signalling. 2017. ↩︎
Adachi Y, et al. ATF6 signaling. Journal of Biochemistry. 2018. ↩︎
Zhao C, et al. PDI up-regulation therapy. Journal of Pharmacology and Experimental Therapeutics. 2018. ↩︎
Woehlbier U, et al. PDI modulators in neurodegeneration. Trends in Pharmacological Sciences. 2019. ↩︎
Johansson AC, et al. CSF PDIA3 as biomarker. Neurology. 2018. ↩︎