Dominant mutations in SOD1 (encoding superoxide dismutase 1) cause amyotrophic lateral sclerosis (ALS) and its hallmark feature, motor neuron death. Now, Su-Chun Zhang and colleagues (Cell Stem Cell doi:10.1016/j.stem.2014.03.004, 3 April 2014) and Kevin Eggan and colleagues (Cell Stem Cell doi:10.1016/j.stem.2014.02.004, 3 April 2014) have independently generated induced pluripotent stem cells (iPSCs) from individuals with SOD1 mutations and investigated early pathological events in motor neurons derived from these iPSCs. Both groups created isogenic controls through TALEN-mediated genetic correction of the SOD1 mutation. Zhang and colleagues found that SOD1-mutant motor neurons exhibited neurofilament aggregation and altered stoichiometry for the neurofilament subunits. They showed that mutant SOD1 binds to the 3′ UTR of the NFL gene and decreases the amount of NFL mRNA produced. Eggan and colleagues characterized transcriptome changes in SOD1-mutant motor neurons and showed that these cells expressed markers of an unfolded protein response and endoplasmic reticulum (ER) stress. They showed that some of these transcriptional changes are also present in motor neurons derived from the iPSCs of individuals with ALS caused by pathogenic repeat expansions in the C9orf72 locus, suggesting that these distinct disease-causing mutations act through common pathways.