Motor Neuron Disease-Associated Loss of Nuclear TDP-43 Is Linked to DNA Double-Strand Break Repair Defects
60 Pages Posted: 12 Apr 2018 Publication Status: Review CompleteMore...
Loss of nuclear TDP-43 has been linked to amyotrophic lateral sclerosis (ALS), which also features increased genome damage in affected neurons. Although TDP-43 binds to DNA, its role in the DNA damage response (DDR) has not been investigated. Here, we report that nuclear TDP-43 is a critical component of the DNA double-strand break (DSB) repair machinery in motor neurons. TDP-43 is rapidly recruited at DSB sites where it stably interact with non-homologous end joining (NHEJ)- mediated DSB repair and DDR factors in spinal motor neurons derived from human neural stem cells. Total or nucleus-specific loss of TDP-43 in motor neurons and C. elegans markedly increased genomic DSBs by impairing NHEJ and sensitized cells to DSB stress. TDP-43 pathology strongly correlated with DSB accumulation and DDR activation in the spinal cord of postmortem ALS patients. Our findings link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease.
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