ALS-associated RNA binding proteins converge on UNC13A transcription through regulation of REST
Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration. We demonstrate that ALS-associated RNA-binding proteins (RBPs)—MATR3, FUS, and hnRNPA1—regulate UNC13A transcription via REST mRNA stabilization. Loss of these RBPs increases REST levels, repressing UNC13A transcription and implicating synaptic dysfunction in ALS pathogenesis. Overall design: We performed RNA-seq using wild-type and CRISPR/Cas9-generated MATR3-, FUS-, hnRNPA1-, and TDP-43-KO SH-SY5Y cell lines. Libraries were prepared using Illumina TruSeq Standard mRNA LT Sample Prep Kit and sequenced using Illumina HiSeq 2500 with paired-end 151 nt reads. Data were processed to identify gene expression changes associated with loss of ALS-related RBPs.