Human induced pluripotent stem cells (iPSC) hold promise for modeling diseases in individual human genetic backgrounds and thus for developing precision medicine. This study generates sensorimotor organoids containing physiologically functional neuromuscular junctions (NMJs) and applies the model to different amyotrophic lateral sclerosis (ALS) subgroups. Using molecular, genomic, and physiological techniques, motor neurons, skeletal muscle, sensory neurons, astrocytes, microglia, and vasculature are identified and characterized. Organoids from ALS individuals and isogenic lines with familial ALS mutations show NMJ impairment, detected by contraction and immunocytochemistry. The model's physiological resolution of the human NMJ synapse, combined with major cellular cohorts, is valuable for understanding ALS pathophysiology.

João D. Pereira, Daniel M. DuBreuil, Anna-Claire Devlin, Aaron Held, Yechiam Sapir, Eugene Berezovski, James Hawrot, Katherine Dorfman, Vignesh Chander, Brian J. Wainger