Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with diverse genetic etiologies. Pathology resulting from the DNA- and RNA-binding protein TDP-43 has been observed in neurodegenerative diseases, including ALS, frontotemporal dementia, Alzheimer’s disease and others. Linares et al. show that suppression of the pre-mRNA splicing factor SYF2 ameliorates neurodegeneration in ALS by improving the activity of TDP-43.