Neuropeptide Y mitigates ER stress–induced neuronal cell death by activating the PI3K–XBP1 pathway

Abstract

The unfolded protein response (UPR) is an evolutionary conserved adaptive reaction for increasing cell survival under endoplasmic reticulum (ER) stress conditions. The UPR signaling pathway is a cellular defense system for dealing ER stress but switches to apoptosis when ER stress is prolonged. The ER stress-associated neuronal cell death pathways have been recognized in the pathogenesis of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s disease. Neuropeptide Y (NPY) has an important role in neuroprotection against neurodegenerative diseases. In this study, we investigated whether NPY has a protective role in ER stress-induced neuronal cell death in SK-N-SH human neuroblastoma cells. An ER stress-inducing chemical, tunicamycin, increased the activities of caspase-3 and -4, whereas pre-treatment with NPY reduced the caspase-3 and -4 activities during ER stress response. In addition, NPY suppressed the activation of three major ER stress sensors in tunicamycin-induced ER stress response. NPY-mediated activation of PI3K increased the nuclear translocation of XBP-1s, which in turn induced the expression of Grp78/Bip. Taken together, our data indicated that NPY has a protective role in ER stress-induced neuronal cell death through activation of the PI3K-XBP1 pathway, and NPY signaling can serve as therapeutic target for ER stress-mediated neurodegenerative diseases.