Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis

Frontiers in Neuroscience

Neuroscience

Michael R. Green¹  Minggang Fang¹  Sara K. Deibler¹  Shahid Banday¹  Alissa L. Nana²  William W. Seeley²  Sarat C. Vatsavayai²  Alexandra Weiss³  Robert H. Brown³  Sandra Almeida³  You Zhou⁴  Fen-Biao Gao⁴ 

[1] Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, United States;Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States;Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, United States;Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, United States;RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, United States;

关键词: amyotrophic lateral sclerosis;    frontotemporal dementia;    TDP-43;    DNA repair;    genomic instability;    homologous recombination;   

DOI  :  10.3389/fnins.2023.1251228

 received in 2023-07-01, accepted in 2023-09-08,  发布年份 2023

来源: Frontiers

【 摘 要 】

A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.

【 授权许可】

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Copyright © 2023 Fang, Deibler, Nana, Vatsavayai, Banday, Zhou, Almeida, Weiss, Brown, Seeley, Gao and Green.