Prof. Krzystof Sobczak - Compounds which alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats in the Fragile X–associated syndrome
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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 (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of noncanonical translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. During the lecture we will discuss the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) and small compounds targeting directly the rCGGexp. 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 cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment. We also identified small compounds, CMBLs, which bind to RNA structure formed by rCGGexp and attenuates translation of toxic FMRpolyG and formation of nuclear inclusions in FXTAS cells. Our results indicate that CMBL4c can reduce FMRpolyG-mediated cytotoxicity and apoptosis. Importantly, its therapeutic potential is also observed once the inclusions are already formed.
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