Dysregulation of RNA processing contributes to multiple neurodegenerative diseases. In this article, Wu et al. demonstrated that nuclear speckle dysfunction represents a converging toxic pathway contributed by both (GGGGCC)n repeat RNA and the noncanonical translation product poly-GR in C9ORF72-FTD/ALS. Impaired nuclear speckle integrity induces RNA mis-splicing and causes neuronal degeneration.