Targeting TDP-43's Conserved Region Shields Neurons in ALS Models

Scientists identify a conserved region (CR; residues 320–340) in TDP-43's low-complexity domain as a drug target. Deleting CR or treating with XL20, a brain-penetrant molecule that binds CR, dampens TDP-43 toxicity, corrects mitochondria-related dysfunction via LLPS, and prolongs survival in ALS mouse models, with positive effects in human mutant TDP-43 motor neurons, all while preserving TDP-43 splicing. XL20 shows CNS penetration and good safety, supporting CR targeting as a therapeutic strategy for TDP-43–related neurodegeneration.