{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:37:02Z","timestamp":1773769022762,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    Mislocalization and aggregation of the DNA\/RNA binding protein, TDP-43, is seen in most cases of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Accumulating DNA damage in neurons is also a common feature of ALS-FTD. TDP-43 has several characterized roles in the regulation of the DNA damage response (DDR). This review systematically explored the relationship between TDP-43, DNA damage and the DNA damage response in various models of ALS-FTD, facilitating comparison of findings between studies using similar models. Twelve peer-reviewed papers, covering eight TDP-43 mutations out of nearly 40, were reviewed and five experimental models included: cell lines, patient-derived iPS cells, organoids, and rodent models, plus post-mortem cortex and spinal cord tissue from ALS-FTD patients. Across the studies and models, depletion of TDP-43 or ALS-linked mutations consistently increased genomic instability. Q331K-expressing cells showed a 2-3-fold reduction in DNA repair activity and a 4-6-fold increase in DDR activation, while\n                    <jats:italic>TDP-43<\/jats:italic>\n                    -depleted cells showed a 20-fold rise in double strand breaks. TDP-43 normally binds to damaged chromatin, participates in early DDR signaling and scaffolds core DNA damage repair factors, including Ku70, XRCC4 and DNA ligase 4. This systematic review and narrative synthesis sheds light on mechanisms that explain how TDP-43 dysfunction impairs genome maintenance. When TDP-43 is mislocalized, mutated or aggregated, these interactions are disrupted, resulting in impaired DNA repair. DNA damage is also caused by increasing R-loops, dysregulation of mismatch repair gene transcription, and sequestering of repair proteins into cytoplasmic inclusions. Upstream DNA damage can further drive TDP-43 mislocalisation, creating a feed-forward loop. Given the ubiquity of TDP-43 pathology across neurodegenerative diseases, targeting the DDR mechanisms affected by TDP-43 may offer new therapeutic opportunities.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2026.1671909","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:35:29Z","timestamp":1773758129000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis"],"prefix":"10.3389","volume":"19","author":[{"given":"Seham","family":"Almalki","sequence":"first","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"Department of Biotechnology, Faculty of Science, Taif University","place":["Taif, Saudi Arabia"]},{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"Birmingham Centre for Neurogenetics, University of Birmingham","place":["Birmingham, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Salama","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"Birmingham Centre for Neurogenetics, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"University Hospitals Birmingham NHS Foundation Trust","place":["Birmingham, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"Birmingham Centre for Neurogenetics, University of Birmingham","place":["Birmingham, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zubair","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"Birmingham Centre for Neurogenetics, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"University Hospitals Birmingham NHS Foundation Trust","place":["Birmingham, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard I.","family":"Tuxworth","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"Birmingham Centre for Neurogenetics, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"University Hospitals Birmingham NHS Foundation Trust","place":["Birmingham, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1671906","DOI":"10.3389\/fnmol.2025.1671906","article-title":"C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review","volume":"18","author":"Almalki","year":"","journal-title":"Front. 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