In this study, we interrogated three different ALS/FTD models, including iPSC-derived cortical and motor neurons, spinal cord organoids, and postmortem sALS and C9-ALS patient-derived brain and spinal cord samples, and identified severe alterations in the nuclear levels and cellular distribution of the four most abundant components of the LINC complex: SUN1, SUN2, Nesprin1, and Nesprin2. Here, SYNE1 is linked to frontotemporal dementia.