iPSC Motor Neurons with Familial ALS Mutations Capture Gene Expression Changes in Postmortem Sporadic ALS Motor Neurons
Held, A.; Adler, M.; Marques, C.; Kavuturu, A. S.; Quadros, A. R. A. A.; Ndayambaje, I. S.; Lara, E.; Ward, M.; Lagier-Tourenne, C.; Wainger, B. J.
Show abstract
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.
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