Targeting the UPR in ALS. Different factors may induce ER dysfunction in ALS. For example, abnormal protein aggregation/misfolding, PDIs inactivation by nitrosylation, ERAD dysfunction, altered vesicle traffic, and/or autophagy defects represent conditions that could induce ER stress and lead to an adaptive stress response known as the unfolded protein response (UPR) at early disease stages. The manipulation of different UPR components has revealed a functional contribution of distinct ER stress signaling events in preclinical models of ALS. Genetic targeting of ASK1 (ASK1−/−), a downstream signaling component of IRE1α, protects against the development of experimental ALS decreasing motor neuron death in the spinal cord of mutant mice [56]. The deletion in the CNS of the transcription factor XBP1 (CNS XBP1−/−) increases the survival of the mutant mice, associated with reduced accumulation of mutant SOD1 aggregates in vivo and enhanced autophagy levels [31]. PERK haploinsufficiency (PERK+/−) enhanced the severity of experimental ALS, associated with elevated levels of neuronal loss and mutant SOD1 aggregation [43]. The deletion of the transcription factor ATF4 (ATF4−/−) in the mutant mice delays the appearance of the symptoms and the extended animal survival. These effects were associated to changes in the ER protein folding network and apoptotic genes [63]. In a pharmacological strategy, the treatment of mutant SOD1 mice with a small molecule that selectively induces eIF2α phosphorylation, salubrinal, protects against disease progression [52]. No manipulation of ATF6 in animal models of ALS has been described.
