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The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

by 1 and 1,2,*
1
Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
2
La Trobe Institute for Molecular Science, Melbourne, VIC 3086, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 3137; https://doi.org/10.3390/ijms19103137
Received: 20 September 2018 / Revised: 9 October 2018 / Accepted: 9 October 2018 / Published: 12 October 2018
(This article belongs to the Special Issue DNA Replication Stress)
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. View Full-Text
Keywords: C9orf72; ALS; motor neuron disease; R loops, nucleolar stress; neurodegeneration C9orf72; ALS; motor neuron disease; R loops, nucleolar stress; neurodegeneration
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MDPI and ACS Style

Konopka, A.; Atkin, J.D. The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2018, 19, 3137. https://doi.org/10.3390/ijms19103137

AMA Style

Konopka A, Atkin JD. The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis. International Journal of Molecular Sciences. 2018; 19(10):3137. https://doi.org/10.3390/ijms19103137

Chicago/Turabian Style

Konopka, Anna; Atkin, Julie D 2018. "The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis" Int. J. Mol. Sci. 19, no. 10: 3137. https://doi.org/10.3390/ijms19103137

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