The emerging role of DNA damage in the pathogenesis of the C9Orf72 repeat expansion in amyotrophic lateral sclerosis

Anna Konopka, Julie D. Atkin*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

19 Citations (Scopus)
14 Downloads (Pure)


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.

Original languageEnglish
Article number3137
Pages (from-to)1-21
Number of pages21
JournalInternational Journal of Molecular Sciences
Issue number10
Publication statusPublished - 12 Oct 2018

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


  • ALS
  • C9orf72
  • Motor neuron disease
  • Neurodegeneration
  • Nucleolar stress
  • R loops


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