Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders. [Display omitted] •Modeling familial ALS (FALS) using iPSC-derived motor neurons•Aberrant gene expression and/or splicing in FALS motor neuron precursor cells•Mis-localization of mutant FUS protein in FALS motor neurons•Increased apoptosis of FALS motor neurons Okano, Yano, and colleagues established iPSCs from two familial ALS patients with the missense mutation in the FUS gene and differentiated them into motor neurons as a novel in vitro model for ALS. Moreover, this model enables the pursuit of correlations and new discovery of molecular pathophysiology in various cell biological phenomena by endogenous mutation in patient-derived motor neurons.