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.
Highlights
Amyotrophic lateral sclerosis (ALS), known as motor neurone disease (MND), is a progressive neurodegenerative disease of motor neurones
Some 5–15% of ALS patients receive a diagnosis of frontotemporal dementia (FTD) and up to 50% of patients experience FTD-like symptoms of some kind [7]
Similar to ALS, at least 10% of FTD cases exhibit autosomal dominant inheritance and up to 40% of cases exhibit some degree of family history
Summary
Amyotrophic lateral sclerosis (ALS), known as motor neurone disease (MND), is a progressive neurodegenerative disease of motor neurones. The C9orf expansion is identified in up to around 6% of apparently sporadic ALS cases and 6% of sporadic FTD This unexpected link to sporadic disease is believed to be partially due to incomplete or inadequate family history information being available and because of reduced penetrance owing to the late onset of ALS and FTD. Since the discovery of C9orf in 2011, it has gradually become clear that significant variability of penetrance exists for the phenotypes associated with this mutation and that modifying mutations and variants in other ALS/FTD-related genes are often present in affected expansion-positive patients [6]. We shall examine the various roles of RNA in C9orf72-related ALS/FTD and consider what this may mean for the understanding of this devastating neurodegenerative disorder and what implications there may be for the design of targeted therapeutics
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