FIGURE 4.

Endoplasmic reticulum stress the UPR and ALS. ALS-associated genes have been implicated in ER stress and the UPR. The ALS-associated genes and their positions within the UPR pathway are indicated in red, as are other ALS-associated defects to the UPR. Briefly, ALS-associated protein aggregates, including C9orf72-related DPR proteins, TDP-43 and SOD1, are sensed by the ER-stress transducers leading to chronic activation of the UPR, caspase-12 cleavage and apoptosis, while disruption of ER/mitochondria contact sites leads to dysfunctional calcium homeostasis and, in turn, elevated ER stress. Finally, mutant SOD1 aggregates interact with Derlin-1, a member of the ERAD pathway, and disrupts the proteasome-dependent degradation of misfolded ER proteins, thus promoting further ER stress. For further details please refer to the main text.