Various types of stress, such as disruption of
calcium homeostasis, inhibition of protein glycosylation and reduction of
disulfide bonds, result in accumulation of misfolded
proteins in the endoplasmic reticulum (ER). The initial cellular response involves removal of such
proteins by the ER, but excessive and/or long-term stress results in apoptosis. In this study, we used a randomized
ribozyme library and ER stress-mediated apoptosis (
tunicamycin-induced apoptosis) in SK-N-SH human
neuroblastoma cells as a selective phenotype to identify factors involved in this process. We identified a
double-stranded RNA-dependent
protein kinase (PKR) as one of the participants in this process. The level of nuclear PKR was elevated, but the level of cytoplasmic PKR barely changed in
tunicamycin-treated SK-N-SH cells. Furthermore,
tunicamycin also raised levels of phosphorylated PKR in the nucleus. We also detected the accumulation of phosphorylated PKR in the nuclei of autopsied brain tissues in
Alzheimer's disease. Thus, PKR might play a role in ER stress-induced apoptosis and in
Alzheimer's disease.