Protein disulfide-isomerase A6

Protein disulfide-isomerase A6 (PDIA6) is a 48 kDa oxidoreductase that functions as a molecular chaperone inhibiting aggregation of misfolded proteins (UniProt: Q15084). It negatively regulates the unfolded protein response (UPR) by binding to and inactivating ERN1 and EIF2AK3 UPR sensors, and participates in platelet aggregation downstream of thrombin and collagen signaling (UniProt: Q15084).

PDIA6 localizes to the endoplasmic reticulum and plays a central role in proteostasis and ER stress responses across diverse tissues. While not annotated in UniProt with inherited disease associations, its regulatory functions in protein folding and UPR signaling implicate it in conditions involving ER stress and protein misfolding.

In Alzheimer's disease, PDIA6 is upregulated in post-mortem brain tissue relative to age-matched controls (mean log2FC = 0.45 across one subcellular fraction; Chaparral AD proteomics). This elevation is consistent with enhanced ER stress responses in AD pathology, where increased misfolded protein burden may necessitate compensatory upregulation of chaperone and UPR regulatory machinery.