ALS-associated RNA-binding proteins promote UNC13A transcription through REST downregulation

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons. Although multiple pathophysiological mechanisms have been identified, no comprehensive understanding of these heterogeneous processes has been achieved. The ALS-associated RNA-binding protein (RBP) TDP-43 has previously been shown to stabilize UNC13A mRNA by preventing cryptic exon inclusion. Here, we show that the ALS-associated RBPs MATR3, FUS, and hnRNPA1 regulate UNC13A expression by targeting the transcriptional repressor REST. These RBPs bind to and downregulate REST mRNA to promote UNC13A transcription. Loss of any of these RBPs in cultured cells or in iPSC-derived motor neurons carrying the ALS-causing FUS P525L mutation leads to REST overexpression, and the same is observed in motor neurons of individuals with familial or sporadic ALS. The functional convergence of four RBPs on the regulation of UNC13A expression underscores the important role of this process for synaptic integrity, and its association with ALS pathogenesis could be relevant for the development of new therapeutic agents.