Figure 7.

ER stress and autophagy in ALS. Different mutations such as those in SOD1, TARDBP and FUS are all able to induce neuronal apoptosis through activation of DDIT3. Both TARDBP and FUS can be included in stress granules in the cytoplasm. Phosphorylation of EIF2S1 mediated by TARDBP and mSOD1 (mutant SOD1) facilitates stress granules formation. Interestingly, either FUS or mSOD1 increases expression of XBP1s but activated XBP1s inhibits autophagic clearance of mSOD1. Moreover, mOPTN (mutant OPTN) also hampers autophagy by inhibiting fusion of autophagosomes with lysosomes. Enhanced autophagic activity induced by autophagic inducers leads to clearance of FUS and TARDBP. Interestingly, SQSTM1 plays a crucial role in packaging TARDBP into autophagosomes.