SRP189030 PRJNA528392 GSE128647 An intramolecular salt bridge linking TDP43's RNA recognition motifs dictates RNA binding, protein stability and TDP43-dependent neurodegeneration The majority of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit neuronal cytoplasmic inclusions rich in the RNA binding protein TDP43. Even so, the relationship between TDP43's RNA binding properties and neurodegeneration remain obscure. Here we show that engineered mutations disrupting a salt bridge between TDP43's RNA recognition motifs interfere with nucleic acid binding and eliminate recognition of native TDP43 substrates. The accumulation of WT TDP43, but not RNA binding-deficient variants, disproportionately affected the abundance and splicing of encoding ribosome and oxidative phosphorylation components. Overall design: TDP43 variants harboring mutations affecting RNA binding were transfected into human embryonic kidney (HEK293T) cells and subjected to RNA-seq to identify transcripts selectively affected by WT TDP43. GSE128647 pubmed 31018129