We have now uncovered convergent mechanisms by which four ALS-associated RBPs regulate the expression of UNC13A. Whereas TDP-43 stabilizes UNC13A mRNA by blocking insertion of a cryptic exon, the loss of MATR3, FUS, or hnRNPA1 gives rise to the transcriptional repression of UNC13A mediated by repressor element-1 silencing transcription factor (REST). Here, REST is linked to amyotrophic lateral sclerosis.