Mutations in TAR DNA-binding protein 43 (TDP43) are associated with amyotrophic lateral sclerosis; however, the precise mechanisms of TDP43-mediated pathogenesis are unclear. The authors show that the specific expression of mutant TDP43 in spinal astrocytes is sufficient to cause progressive motor neuron degeneration, muscular atrophy and paralysis in rats, through mechanisms involving downregulation of 'neuroprotective' genes such as those encoding glutamate transporters and upregulation of 'neurotoxic' genes such as lipocalin 2 (Lcn2).