In persistent ER stress, UPR can lead to C/EBP homologous protein-induced ROS accumulation and apoptosis through the sustained phosphorylated state of eIF2α and p53-dependent pathways, for which PHLDA3 has been shown to serve as an effector.10,25 Although neither overexpression nor KD of PHLDA3 in control or ALS astrocytes affected cell viability, KD did reduce ROS production in ALS astrocytes characterized by proteostasis disturbances and ER stress. Here, TP53 is linked to amyotrophic lateral sclerosis.