Our in vivo model of c9FTD/ALS, the first to robustly recapitulate hallmark features derived from both sense and antisense C9orf72 repeat-associated transcripts, and to display neurodegeneration and behavioral impairments, provides novel insight into the mechanism driving TDP-43 proteinopathy in c9FTD/ALS. Here, C9orf72 is linked to amyotrophic lateral sclerosis.