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

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.

C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?

“…Variant 1 (V1; NM_145005.7) and variant 3 (V3; NM_001256054.3), starting from exon 1a, contain the repeat expansion in the first intron, while variant 2 (V2; NM_018325.5) initiates its coding region from exon 1b and harbors the expansion in the promoter region [ 10 , 30 , 42 ]. In addition to these three conventional transcripts, at least two non-coding transcript variants (lncRNAs) have been described, including their natural antisense transcripts [ 30 , 41 , 93 ]. Due to the alternative transcription start sites, exon 1c is the first of transcript variant 4 (V4) and 5 (V5) with V5 representing a truncated form of V4 (Fig.…”

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

“…SOD1 mutations are present in about 15 to 20% of families with ALS [226]. In addition, a hexanucleotide repeat expansion in the first intron/promoter region of the lncRNA C9ORF72 is the most common genetic cause of ALS, present in 40% of familiar cases [227]. Mechanistically, the RNA toxicity of C9ORF72-related ALS is based on the direct sequestration of important RNA binding proteins by the hexanucleotide repeat and RAN translation into dipeptide repeats.…”

Identification of Molecular Signatures in Neural Differentiation and Neurological Diseases Using Digital Color-Coded Molecular Barcoding

“…Lastly, ALS molecular signature has been performed by digital color-coded barcoding approach as well. The hexanucleotide GGGGCC repeat expansion in the first intron/promoter region (noncoding region) of the C9ORF72 gene is the most common genetic cause of this pathology [ 57 , 58 ]. Using 50-mer NanoString probes, the levels of the three C9ORF72 RNA variants were determined in samples of patient-derived human brain tissue, ALS fibroblasts, iPSCs, and iPSC-derived neurons (iPSNs).…”