Thus, our data provide in vivo evidence that 1) ALS-linked mutant TDP-43 causes age-dependent defects in nuclear membrane morphology (as indicated by RanGAP1 staining) not only in mouse motor neurons (correlating with motor functionality), but also in ALS patients harboring TDP-43 mutations, and 2) motor neuron-specific reduction of mutant TDP-43 significantly delays the appearance of such defects and of motor performance deficits. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.