C9orf72 gene transcriptional machinery (C9orf72)

The C9orf72 gene transcriptional machinery refers to the complex of proteins and regulatory elements, including RNA polymerase II and elongation factors like Spt5 and the PAF1 complex, that govern the expression of the C9orf72 gene. In its healthy state, the C9orf72 protein is involved in critical cellular processes such as endosomal trafficking and autophagy (UniProt Q96LT7). However, a hexanucleotide repeat expansion (GGGGCC) within the gene's first intron is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). This mutation results in a toxic gain-of-function through the formation of RNA foci and the production of dipeptide repeat proteins (DPRs) via repeat-associated non-AUG (RAN) translation. Therapeutic interventions target this machinery to selectively reduce the transcription of the expanded repeats or degrade the resulting toxic transcripts. Current drug development efforts focus on antisense oligonucleotides and small molecules that can modulate these transcriptional processes to alleviate neurodegeneration while maintaining sufficient levels of the functional wild-type protein.

Other names

C9orf72 regulatory complexC9orf72 transcription complexChromosome 9 open reading frame 72 transcriptional machineryC9orf72 repeat expansion transcription unit

Therapeutic agents targeting the C9orf72 transcriptional machinery primarily utilize antisense oligonucleotides (ASOs) to induce RNase H-mediated degradation of repeat-containing pre-mRNA or employ small molecules to selectively inhibit transcription elongation factors, such as Spt5, that are required for the expression of the expanded hexanucleotide repeats.