ER stress and the selective neuronal vulnerability in ALS. (a) Schematic representation of ER stress levels (green label) and UPR activation (purple label) in the two subgroups of neurons that have been identified in mutant SOD1 mouse models of ALS: one population that dies early (vul, vulnerable, blue) and another that dies later during disease progression (res, resistant, red). Activation of stress markers is a common feature detected in Vul and Res motoneurons. However, vul motoneurons express these stress markers earlier than de res neurons. The UPR is activated in both subgroups of neurons. UPR activation also correlates with microglial activation in both groups. It is not known what determines the resistance of Res cells in the disease. (b) Time-course of ER stress levels and UPR activation in familial ALS models. ER stress and protein disturbance increase during ALS progression (“ER dysfunction,” black dashed line). During the presymptomatic stage of the disease, UPR activation might represent an adaptive response that attenuates ER stress levels. Over time, the stress condition exceeds the capacity of the cell to manage protein folding stress and pro-apoptotic pathways are activated. This shift “onset threshold” in UPR signaling regulation could be associated with motoneuron dysfunction/loss and the onset of the disease. During the symptomatic stage, a strong and chronic UPR activation occurs. (c) Possible therapeutic approaches to modulate the UPR in ALS. An earlystage preventive treatment may modulate UPR levels to enhance the adaptive capacity of motoneurons and reduce ER stress levels or other proteostasis disturbances. This may delay disease onset and disease evolution “healthy window”. The therapeutic approaches include gene therapy to deliver active UPR components and the use of smallmolecules that selectively activate specific UPR signaling branches (pharmacologic approaches) or act as chemical chaperones to alleviate global ER stress. This reduction in ER stress levels in motoneurons could also be achieved by modulating glial UPR.
