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Review
. 2018 Oct 12;19(10):3137.
doi: 10.3390/ijms19103137.

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

Anna Konopka  1 , Julie D Atkin  2   3
Affiliations
Review

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

Anna Konopka et al. Int J Mol Sci. .

Abstract

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.

Keywords: ALS; C9orf72; R loops, nucleolar stress; motor neuron disease; neurodegeneration.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Scheme illustrating mechanisms by which genomic integrity is disrupted by the C9orf72 repeat expansion in ALS. Cells are exposed to exogenous and endogenous sources of DNA damage, such as normal cellular metabolism, the formation of R-loops, UV light exposure, ionising radiation, chemical exposure, and replication errors. In normal physiological conditions, the integrity of the genome is preserved by safeguarding mechanisms: the DDR and the nucleolus. However, in ALS, transcription of the C9orf72 repeat expansion leads to the production of expanded RNA transcripts. Furthermore, DPRs and abnormal DNA structures, such as R-loops, hairpins, and G-quadruplexes, are formed. These conformations compromise the normal cellular protective mechanisms, leading to persistent DNA damage and loss of genomic integrity.
Figure 2
Figure 2
Mechanisms of amyotrophic lateral sclerosis (ALS) pathogenesis induced by the chromosome 9 open reading frame 72 (C9orf72) repeat expansion. The C9orf72 repeat expansion forms abnormal nucleic acid structures, including R-loops, which perturb DNA repair processes involving ATM, and probably other mechanisms. The expanded RNA forms foci and sequesters RNA binding proteins, leading to dysfunction in RNA processing. The C9orf72 DPRs, produced by RAN translation, also accumulate in the nucleolus, leading to perturbations in nucleolar function, including DNA repair processes, ribosomal biogenesis, and APE-dependent mechanisms (including oxidative stress). They also impair DNA repair by p62-dependent mechanisms. Together, these events result in the accumulation of DNA damage, genome instability, and motor neuron death.
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