Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects

TLDR

ALS is a fatal motor neuron disease lacking cure, with ~95 % of patients showing TDP‑43 mislocalization, yet the mechanisms linking TDP‑43 pathology to neuronal death remain unclear. The study aims to determine whether nuclear loss of TDP‑43 impairs DNA double‑strand break repair in ALS motor neurons. The authors show that TDP‑43 normally contributes to the DNA damage response, and its nuclear depletion in motor neurons leads to defective double‑strand break repair. They found that TDP‑43 loss in ALS motor neurons is associated with impaired DNA repair, indicating that targeting DNA repair pathways could be therapeutic.

Abstract

Significance Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure to date. About 95% of ALS patients feature abnormalities in the RNA/DNA binding protein TDP-43, involving its nucleus-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. Here, we report that TDP-43 participates in the DNA damage response and its nuclear clearance in motor neurons causes DNA double-strand break repair defects in ALS. Our findings uncover a link between TDP-43 pathology and impaired DNA repair, and suggest potential avenues for DNA repair-targeted therapies for TDP-43–ALS.