The UPR emanates from the endoplasmic reticulum (ER) and is transduced by three ER‐resident transmembrane proteins, namely IRE1α, ATF6α and PERK, whose signalling aims at restoring ER protein homeostasis (proteostasis) through transcriptional and post‐transcriptional mechanisms.7 In ALS patients’ tissues, the UPR is activated predominately in the spinal cord,8 where we have observed a profound activation of IRE1α‐XBP1s and ATF6 signalling arms and their target genes mainly involved in protein degradation and protein folding processes.9, 10, 11. The gene discussed is ERN1; the disease is amyotrophic lateral sclerosis.