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

A hexanucleotide repeat expansion in the first intron/promoter region of is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both sense and antisense transcripts exist at the locus but the function of the antisense lncRNA is unknown. RNA toxicity of the transcribed repeat expansion has been implicated in the pathogenesis of -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 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 -related ALS/FTD. Furthermore, the mechanisms of RNA dysregulation exemplified by -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.