{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T20:02:25Z","timestamp":1790539345696,"version":"4.1.0"},"reference-count":176,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T00:00:00Z","timestamp":1539302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["10305133, 1086887, 1095215"],"award-info":[{"award-number":["10305133, 1086887, 1095215"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.<\/jats:p>","DOI":"10.3390\/ijms19103137","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T10:54:03Z","timestamp":1539341643000},"page":"3137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"19","author":[{"given":"Anna","family":"Konopka","sequence":"first","affiliation":[{"name":"Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine &amp; Health Sciences, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie D","family":"Atkin","sequence":"additional","affiliation":[{"name":"Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine &amp; Health Sciences, Macquarie University, Sydney, NSW 2109, Australia"},{"name":"La Trobe Institute for Molecular Science, Melbourne, VIC 3086, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,12]]},"reference":[{"key":"ref_1","first-page":"381","article-title":"DNA damage checkpoint, damage repair, and genome stability","volume":"33","author":"Liu","year":"2006","journal-title":"Yi Chuan Xue Bao"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/NEN.0b013e31816ff780","article-title":"DNA damage and repair: Relevance to mechanisms of neurodegeneration","volume":"67","author":"Martin","year":"2008","journal-title":"J. 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