Unmasking the skiptic task of TDP-43.

The mechanism by which mutations in TAR DNA‐binding protein 43 (TDP‐43) cause neurodegeneration remains incompletely understood. In this issue of , Fratta (2018) describe how a point mutation in the C‐terminal low complexity domain of TDP‐43 leads to the skipping of otherwise constitutively conserved exons. , this mutation triggers late‐onset progressive neuromuscular disturbances, as seen in amyotrophic lateral sclerosis (ALS), suggesting that TDP‐43 splicing gain‐of‐function contributes to ALS pathogenesis.