The protein disulfide-isomerases (PDIs) are generally localized to the endoplasmic reticulum (ER) where they mediate thiol–disulfide interchanges, which is a critical process during post-translational protein folding [66], and PDIA3 is markedly upregulated in most common neurodegenerative diseases, highlighting ER as an emerging driver of neurodegeneration [67, 68]. This evidence concerns the gene P4HB and neurodegenerative disease.