Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats.

ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5'UTR. The RNA containing expanded CGG repeats (rCGG^exp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGG^exp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cy

SUBMITTER: Derbis M 

PROVIDER: S-EPMC7904788 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature