TDP-43 mutations-induced defects in miRNA biogenesis and cytotoxicity by differentially obstructing Dicer activity in Drosophila and in vitro

Mutations in the DNA/RNA-binding protein 43 (TDP-43) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). As an RNA-binding protein, TDP-43 plays a diverse physiological role in RNA processing and is potentially involved in the pathological progression caused by disease mutations. However, the precise mechanisms linking RNA dysregulation and TDP-43 mutations, which propel disease progression, are not yet fully understood. Here, we demonstrate that TDP-43 and its Drosophila homolog, TBPH, whose mutations crucially perturb Dicer presentation, result in dysregulated miRNA profiles. Genetically modulating the expression or pharmacologically activating Dicer implies unique interactions of TDP-43 A315T and M337V with the Dicer protein, suggesting a specific mechanism of C-terminal disease mutations contributes to the pathological process. Unlike TDP-43 A315T, the M337V mutation causes the assembly of aggregates and reorganizes but functionally preserves the Dicer activity in miRNA processing. Mutations in TDP-43 disrupt miRNA biogenesis by hindering its interaction with Dicer, leading to cytotoxicity and providing mechanistic insight into the pathogenic mutations associated with ALS-FTD.