The observed synaptic alterations were strongly conserved in sporadic and C9orf72-fALS patients and could be reliably reproduced in a heterogeneous panel of ALS hiPSC-derived MNs, revealing the synaptic microenvironment as a valid target for the future development of novel therapeutic strategies against MNs degeneration. The gene discussed is C9orf72; the disease is amyotrophic lateral sclerosis.