Next Article in Journal
The Role of the TGFβ Receptor Signaling Pathway in Adult Beta Cell Proliferation
Next Article in Special Issue
Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress
Previous Article in Journal
Relationship between Serum BDNF Levels and Depressive Mood in Subacute Stroke Patients: A Preliminary Study
Previous Article in Special Issue
Movement of the RecG Motor Domain upon DNA Binding Is Required for Efficient Fork Reversal
Article Menu
Issue 10 (October) cover image

Export Article

Open AccessReview
Int. J. Mol. Sci. 2018, 19(10), 3137; https://doi.org/10.3390/ijms19103137

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

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.
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)
Full-Text   |   PDF [5046 KB, uploaded 12 October 2018]   |  

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. View Full-Text
Keywords: C9orf72; ALS; motor neuron disease; R loops, nucleolar stress; neurodegeneration C9orf72; ALS; motor neuron disease; R loops, nucleolar stress; neurodegeneration
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top