ALS-associated RNA binding proteins converge on UNC13A transcription through regulation of REST

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Although multiple pathophysiological mechanisms have been identified, a unified molecular basis for ALS has remained elusive. The ALS-associated RNA binding protein (RBP) TDP-43 has previously been shown to stabilize UNC13A mRNA by preventing cryptic exon inclusion. We here show that three ALS-associated RBPs--MATR3, FUS, and hnRNPA1--regulate UNC13A expression by targeting the silencing transcription factor REST. These three RBPs bind to and downregulate REST mRNA and thereby promote UNC13A transcription. REST overexpression was detected not only in response to the loss of each of these three RBPs in cultured cells but also in motor neurons of individuals with familial or sporadic ALS. The functional convergence of four RBPs on the regulation of UNC13A, a gene essential for synaptic transmission, highlights a pivotal contribution of these proteins to maitainance of synaptic integrity. Our findings thus provide key insight into ALS pathogenesis and a basis for the development of new therapeutic agents.