Targeting TDP-43 is neuroprotective in amyotrophic lateral sclerosis
TAR DNA-binding protein 43 (TDP-43) has been implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) but effective therapies targeting TDP-43 neurotoxicity remain elusive.
The researchers in this study show that deletion of the conserved α-helical region spanning residues 320–340 (conserved region or CR) suppressed TDP-43-induced neuronal death.
They also identified a small molecule via structure-based virtual screening and show that the brain-penetrant XL20 engages CR and confers neuroprotection without affecting TDP-43 splicing activity.
Mechanistically, targeting CR suppressed TDP-43 mitochondrial localization and restored mitochondrial function, likely through liquid–liquid phase separation.
