1. Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis
- Author
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Fang, Minggang, Deibler, Sara K, Nana, Alissa L, Vatsavayai, Sarat C, Banday, Shahid, Zhou, You, Almeida, Sandra, Weiss, Alexandra, Brown, Robert H, Seeley, William W, Gao, Fen-Biao, and Green, Michael R
- Subjects
Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Biotechnology ,Orphan Drug ,Stem Cell Research ,Rare Diseases ,Neurodegenerative ,Dementia ,Brain Disorders ,ALS ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Acquired Cognitive Impairment ,Genetics ,Stem Cell Research - Induced Pluripotent Stem Cell ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,amyotrophic lateral sclerosis ,frontotemporal dementia ,TDP-43 ,DNA repair ,genomic instability ,homologous recombination ,Cognitive Sciences ,Biological psychology - Abstract
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.
- Published
- 2023