Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. Most commonly exhibited symptoms include muscular weakness and atrophy. Clinical manifestations begin in adult age and the disease progresses until eventually, death occurs due to respiratory system failure, on average around 3-5 years after clinical onset. The majority of ALS cases are sporadic, with no previously recorded family history of the disease, while a minor proportion of cases are familial. Genes most commonly implicated in ALS are C9orf72, SOD1, FUS and TDP-43. FUS is an RNA/DNA binding protein involved in multiple cellular processes, including transcription regulation, splicing, RNA transport and degradation. Most ALS mutations in FUS are found in the nuclear localization signal, a domain responsible for import of FUS into the nucleus. Mutations in the NLS disrupt FUS import into the nucleus and cause FUS to aggregate within the cytoplasm. ALS is considered to be a distal axonopathy, and the dying-back hypothesis proposes that it originates in the neuromuscular junctions and progresses retrogradely, implicating the involvement of skeletal muscle in disease pathogenesis. The FusΔNLS mutant mice are an adequate model for FUS-ALS as their mutation mimicks those in ALS patients by preventing the transcription of the NLS. The mutation can be fully reversed to wild-type, and its reversal in just the skeletal muscle cells allows the study of non-cell-autonomous contribution of muscle tissue to ALS. FusΔNLS mice exhibit mild but progressive motor deficits, motor axon loss as well as muscular atrophy. Number and area of muscle fibers are slightly reduced, and signs of denervation in motor neurons are also present, as indicated by the reduction in axon numbers. Reversal of the mutation in skeletal muscle partially rescues some phenotypes. The findings suggest that ALS does indeed arise at least in part due to non-cell-autonomous mechanisms of skeletal muscle.