Several pathways perturbed in human motor neurons derived from individuals with amyotrophic lateral sclerosis (ALS) are described in a recent report in Cell Stem Cell (14, 781–795, 2014).

Mutations in the gene encoding superoxide dismutase 1 (SOD1) as well as hexanucleotide repeat expansions at the C9orf72 locus have been associated with ALS. Kevin Eggan and his colleagues generated induced pluripotent stem cells (iPSCs) from two individuals with ALS harboring the same SOD1 (A4V) mutation and differentiated them into spinal motor neurons. The authors observed an increase in apoptosis and altered morphology in these cells, which was corrected by restoration of wild-type SOD1 expression via zinc finger nuclease–mediated gene targeting. RNA sequencing analysis of iPSC-derived mutant motor neurons and isogenic control iPSC-derived motor neurons revealed transcriptional changes in mutant cells in several pathways, including oxidative stress, mitochondrial function and induction of endoplasmic reticulum stress and the unfolded protein response. Using iPSCs derived from individuals with expansions in the C9orf72 locus, the authors identified a subset of genes that are commonly altered, including those encoding catalase, mitochondrial transporters and the protein chaperone DNAJC12.

Another study in the same journal also modeling ALS in iPSCs with SOD1 mutations revealed neurofilament aggregation as an early event in ALS (Cell Stem Cell 14, 796–809, 2014). Together, these studies indicate the promise of iPSCs for mechanistic understanding of ALS and potential identification of therapeutic targets.