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Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction

Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction
Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction
A hexanucleotide repeat expansion in the first intron/promoter region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both sense and antisense transcripts exist at the C9orf72 locus but the function of the antisense lncRNA is unknown. RNA toxicity of the transcribed repeat expansion has been implicated in the pathogenesis of C9orf72-related ALS/FTD, not only through direct sequestration of important RNA binding proteins but also indirectly through non-ATG dependent translation into dipeptide repeats. Formation of RNA/DNA hybrid R-loops may also play a key role in the pathogenesis of this condition and this mechanism could provide a link between the repeat expansion, DNA damage, repeat instability and deficiency of RNA binding proteins. Non-coding C9orf72 antisense transcripts could also act to epigenetically regulate gene expression at the locus. The potential effects of such non-coding RNAs should be considered in the design of antisense oligonucleotide therapeutics for C9orf72-related ALS/FTD. Furthermore, the mechanisms of RNA dysregulation exemplified by C9orf72-related disease may help illustrate more broadly how a “perfect storm” of dysfunction occurs in ALS/FTD and how targeting these factors could lead to corrective or preventative therapies
2468-0540
178-187
Douglas, Andrew G.l.
2c789ec4-a222-43bc-a040-522ca64fea42
Douglas, Andrew G.l.
2c789ec4-a222-43bc-a040-522ca64fea42

Douglas, Andrew G.l. (2018) Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction. Non-coding RNA Research, 3 (4), 178-187. (doi:10.1016/j.ncrna.2018.09.001).

Record type: Article

Abstract

A hexanucleotide repeat expansion in the first intron/promoter region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both sense and antisense transcripts exist at the C9orf72 locus but the function of the antisense lncRNA is unknown. RNA toxicity of the transcribed repeat expansion has been implicated in the pathogenesis of C9orf72-related ALS/FTD, not only through direct sequestration of important RNA binding proteins but also indirectly through non-ATG dependent translation into dipeptide repeats. Formation of RNA/DNA hybrid R-loops may also play a key role in the pathogenesis of this condition and this mechanism could provide a link between the repeat expansion, DNA damage, repeat instability and deficiency of RNA binding proteins. Non-coding C9orf72 antisense transcripts could also act to epigenetically regulate gene expression at the locus. The potential effects of such non-coding RNAs should be considered in the design of antisense oligonucleotide therapeutics for C9orf72-related ALS/FTD. Furthermore, the mechanisms of RNA dysregulation exemplified by C9orf72-related disease may help illustrate more broadly how a “perfect storm” of dysfunction occurs in ALS/FTD and how targeting these factors could lead to corrective or preventative therapies

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Accepted/In Press date: 8 September 2018
e-pub ahead of print date: 10 September 2018
Published date: December 2018

Identifiers

Local EPrints ID: 426854
URI: http://eprints.soton.ac.uk/id/eprint/426854
ISSN: 2468-0540
PURE UUID: b956637e-581f-4ef4-8106-854110da228a
ORCID for Andrew G.l. Douglas: ORCID iD orcid.org/0000-0001-5154-6714

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Date deposited: 14 Dec 2018 17:30
Last modified: 26 Nov 2021 02:55

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