iPSC Motor Neurons with Familial ALS Mutations Capture Gene Expression Changes in Postmortem Sporadic ALS Motor Neurons

Motor neuron degeneration, the defining feature of ALS, is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of iPSCs harboring different familial ALS mutations, we assess the capacity of iPSC-derived spinal motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human post-mortem neurons. At surprisingly early time points, differentially regulated genes in iPSC-derived spinal motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from postmortem spinal cords. The extent of dysregulation correlates well between iPSC-derived and bona fide spinal motor neurons. In iPSC-derived spinal motor neurons, but not other derived cell types, we detect downregulation of genes affected by TDP-43-dependent aberrant splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology and occurs without evidence of TDP-43 mislocalization or protein level alteration.