Fig. 1

Pathogenesis of TARDBP-, FUS-, SOD1- and C9OR72-associated ALS. a TARDBP mutations act through both loss-of-function and gain-of-function mechanisms. Mutant (Mt) TDP-43 proteins inhibit normal TDP-43 binding to pre-mRNA and generate TDP-43 inclusions in the cytoplasm. b Like TDP-43, FUS mutations act through both loss-of-function and gain-of-function mechanisms. Mutant FUS proteins cause loss-of-function by inhibiting normal FUS binding to pre-mRNA. c SOD1 mutations act through a gain-of-function mechanism. Mutant SOD1 dimer accumulation in the cytoplasm leads to prune-like toxin production and Golgi apparatus stress, and generation of mitochondrial reactive oxygen species (ROS), leading to mitochondrial destruction. d The C9ORF72 mutation acts through a gain-of-function mechanism. GGGGCC[G4C2] translocates to the cytosol, translates to form aggregates of poly (GP) DPRs, and misfolds to form aggregates of ubiquitinated RNA aggregates associated with TDP-43 or FUS proteins. Both proteins mediate neuronal toxicity. Cytosol vacuolization (vac) is caused by all the above-mentioned mutations