C9orf72 hexanucleotide repeat sense RNA

C9orf72 hexanucleotide repeat sense RNA refers to RNA transcripts containing expanded GGGGCC hexanucleotide repeats (sense strand) from the C9orf72 gene locus. The abnormal expansion of this repeat in the non-coding region (intron 1) is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)[1][3][4]. These expanded sense repeat RNAs can form stable secondary structures such as G-quadruplexes, which sequester multiple RNA-binding proteins, leading to the formation of nuclear RNA foci—a pathognomonic feature in affected neurons[1][3]. Sequestration of RNA-binding proteins affects various aspects of RNA processing and splicing, contributing to cellular toxicity. Besides, these repeat RNAs can undergo repeat-associated non-ATG (RAN) translation, producing dipeptide repeat proteins which aggregate and further contribute to neurodegeneration[4]. Strategies targeting the sense RNA focus on antisense oligonucleotides (ASOs) that bind to the expanded sequence and induce its degradation or block its pathogenic interactions, as well as small molecules that stabilize the RNA's structure and prevent the sequestration of RNA-binding proteins[3][7]. Quantification of nuclear RNA foci in patient-derived samples and identification of specific dipeptide repeat proteins serve as biomarkers for disease diagnosis and monitoring therapeutic efficacy[4]. Due to its direct role in ALS and FTD, this sense RNA is considered a therapeutic molecular target, but targeting such sequences involves specific safety and technical challenges such as off-target effects and the necessity to preserve normal gene function[3][4].

Other names

C9orf72 sense RNAchromosome 9 open reading frame 72 sense transcriptsense GGGGCC RNAC9orf72 repeat expansion sense strand

Inhibition/targeted degradation of sense RNA foci using antisense oligonucleotides; Blocking sequestration of RNA-binding proteins by small molecules