Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling.

The endoplasmic reticulum (ER)-stress-induced cascade events are implicated in Parkinson's disease (PD). The discovery of drug candidates to protect dopaminergic (DA) neurons from ER-stress-induced oxidative damage is important to resolve the pathological aspects of PD and modify its progress. In this study, we found that a recently identified unfolded protein response (UPR) modulator, azoramide, showed protective effects on patient induced pluripotent stem cells-derived midbrain DA neurons with the homozygous phospholipase A2 group 6 (PLA2G6) D331Y mutant. A series of PD-related cascade events such as ER stress, abnormal calcium homeostasis, mitochondrial dysfunction, increase of reactive oxygen species, and apoptosis were observed in PLA2G6 D331Y mutant DA neurons, whereas azoramide significantly protected PLA2G6 D331Y mutant DA neurons against these events. The beneficial effects of azoramide were abolished by treatment with a cAMP-response element binding protein (CREB) inhibitor. Our results suggest that azoramide is a potential neuroprotectant against DA neuron damage via restoring ER function and the CREB signaling.