A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G₄C₂)^exp in c9ALS/FTD via the nuclear RNA exosome.

ABSTRACT: A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G₄C₂)^exp, causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G₄C₂)^exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a

SUBMITTER: Bush JA 

PROVIDER: S-EPMC9860304 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature