iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons

Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced pluripotent stem cells (iPSCs) harboring different familial ALS mutations, we assess the capacity of iPSC-derived lower motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human postmortem neurons. At early time points, differentially regulated genes in iPSC-derived lower motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from ALS compared with control postmortem spinal cords. For genes altered in both the iPSC model and bona fide human lower motor neurons, expression changes correlate between the two populations. In iPSC-derived lower motor neurons, but not other derived cell types, we detect the downregulation of genes affected by TDP-43-dependent splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology. [Display omitted] •fALS iPSC LMNs capture one-third of gene expression changes in postmortem sALS LMNs•iPSC LMNs, but not other neurons, captured postmortem LMN gene expression changes•Dysregulated genes in fALS iPSC-LMNs include TDP-43 splicing targets•RNA clearance may be disrupted in postmortem LMNs but intact in iPSC LMNs Amyotrophic lateral sclerosis causes motor neuron degeneration but leaves most other neurons intact. Held et al. find that familial ALS mutations cause distinct RNA profiles in iPSC-derived motor neurons compared with other cell types and that fALS iPSC motor neurons capture gene expression changes in postmortem sporadic ALS motor neurons.