In this study, we show that selective loss of Ranbp2 in motoneurons in mice phenocopies prominent pathophysiological ALS traits, such as hindlimb paralysis, weight loss and respiratory distress, which culminate with the premature death of SLICK-H::Ranbp2flox/flox mice. This evidence concerns the gene RANBP2 and amyotrophic lateral sclerosis.