DNA repair

Pathology

DNA damage

Neuroscience

Mitochondrial DNA

Disease

Biology

Gene

Nuclear DNA

Cytoplasm

Motor neuron

Neurodegeneration

Cell nucleus

Amyotrophic lateral sclerosis

Cell biology

Genetics

Medicine

Proceedings of the National Academy of Sciences

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.

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