An Intramolecular Salt Bridge Linking TDP43's RNA Recognition Motifs Dictates RNA Binding 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. These same mutations dramatically destabilize TDP43, alter its subcellular localization and abrogate TDP43-dependent neurodegeneration. Worms harboring homologous TDP-1 mutations phenocopy knockout strains, confirming the necessity of the salt bridge residues for TDP43 function. Moreover, the accumulation of functional TDP43, but not RNA binding-deficient variants, disproportionately affects the abundance and splicing of transcripts encoding oxidative phosphorylation and ribosome components. These studies demonstrate the significance of the salt bridge in sustaining TDP43 stability and RNA binding specificity, factors that are crucial for neurodegeneration arising from TDP43 deposition in ALS and FTD.