Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2ALS pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2ALS model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2ALS and other ER stress-related conditions.
