Exon array analysis of control vs. FALS MPC

To assess RNA regulation in FALS for gene expression and alternative processing of RNA in the motor neuron precurssors (MPCs) Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms that lead to the initiation and progression of this disease 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 the isogenic iPSCs with the homozygous FUS H517D mutation obtained by genome editing from the healthy control iPSCs. These cell-derived motor neurons mimicked several neurodegenerative phenotypes. A part of the mutant FUS protein was localized outside the nucleus and co-localized with stress granules under stress conditions. Moreover, FALS motor neurons showed more apoptotic activity than did control motor neurons. Exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq data sets 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. RNA from each 3 control and 6 FALS-derived MPCs. One array per biological replicate.