Here, we show that selective loss of NPC components, particularly the scaffold proteins NUP107 and NUP93, and FG-repeat-containing components—is a consistent finding across ALS postmortem spinal cord, SOD1^G93A and TDP-43 mutant mouse models, and human cell systems.CRISPR-mediated depletion of NUP107 in human cells triggers hallmark features of ALS pathology, including cytoplasmic TDP-43 mislocalization, increased phosphorylation, and autophagy dysfunction. Here, NUP93 is linked to amyotrophic lateral sclerosis.