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

Research output: Contribution to journalReview articleResearchpeer-review

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.

LanguageEnglish
Article number3137
Pages1-21
Number of pages21
JournalInternational Journal of Molecular Sciences
Volume19
Issue number10
DOIs
Publication statusPublished - 12 Oct 2018

Fingerprint

pathogenesis
Chromosomes, Human, Pair 9
chromosomes
Amyotrophic Lateral Sclerosis
Chromosomes
Open Reading Frames
DNA Damage
emerging
DNA
deoxyribonucleic acid
damage
expansion
disorders
Neurodegenerative diseases
G-Quadruplexes
microsatellites
Frontotemporal Dementia
Gene encoding
genome
Dipeptides

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.

Keywords

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

Cite this

@article{71282718ca754cd9871c5a2a2ea3b9c3,
title = "The emerging role of DNA damage in the pathogenesis of the C9Orf72 repeat expansion in amyotrophic lateral sclerosis",
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, Motor neuron disease, Neurodegeneration, Nucleolar stress, R loops",
author = "Anna Konopka and Atkin, {Julie D.}",
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.",
year = "2018",
month = "10",
day = "12",
doi = "10.3390/ijms19103137",
language = "English",
volume = "19",
pages = "1--21",
journal = "International Journal of Molecular Sciences",
issn = "1422-0067",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",

}

The emerging role of DNA damage in the pathogenesis of the C9Orf72 repeat expansion in amyotrophic lateral sclerosis. / Konopka, Anna; Atkin, Julie D.

In: International Journal of Molecular Sciences, Vol. 19, No. 10, 3137, 12.10.2018, p. 1-21.

Research output: Contribution to journalReview articleResearchpeer-review

TY - JOUR

T1 - The emerging role of DNA damage in the pathogenesis of the C9Orf72 repeat expansion in amyotrophic lateral sclerosis

AU - Konopka, Anna

AU - Atkin, Julie D.

N1 - 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.

PY - 2018/10/12

Y1 - 2018/10/12

N2 - 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.

AB - 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.

KW - ALS

KW - C9orf72

KW - Motor neuron disease

KW - Neurodegeneration

KW - Nucleolar stress

KW - R loops

UR - http://www.scopus.com/inward/record.url?scp=85054892420&partnerID=8YFLogxK

U2 - 10.3390/ijms19103137

DO - 10.3390/ijms19103137

M3 - Review article

VL - 19

SP - 1

EP - 21

JO - International Journal of Molecular Sciences

T2 - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 10

M1 - 3137

ER -