Browsing by Author "Sobczak, Krzysztof"
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Item Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation(Oxford University Press, 2021) Konieczny, Patryk; Mukherjee, Sanjukta; Stepniak-Konieczna, Ewa; Taylor, Katarzyna; Niewiadomska, Daria; Piasecka, Agnieszka; Walczak, Agnieszka; Baud, Anna; Dohno, Chikara; Nakatani, Kazuhiko; Sobczak, KrzysztofFragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a limited expansion of CGG repeats in the FMR1 gene. Degeneration of neurons in FXTAS cell models can be triggered by accumulation of polyglycine protein (FMRpolyG), a by-product of translation initiated upstream to the repeats. Specific aims of our work included testing if naphthyridine-based molecules could (1) block FMRpolyG synthesis by binding to CGG repeats in RNA, (2) reverse pathological alterations in affected cells and (3) preserve the content of FMRP, translated from the same FMR1 mRNA. We demonstrate that cyclic mismatch binding ligand CMBL4c binds to RNA structure formed by CGG repeats and attenuates translation of FMRpolyG and formation of nuclear inclusions in cells transfected with vectors expressing RNA with expanded CGG repeats. Moreover, our results indicate that CMBL4c delivery can reduce FMRpolyG-mediated cytotoxicity and apoptosis. Importantly, its therapeutic potential is also observed once the inclusions are already formed. We also show that CMBL4c-driven FMRpolyG loss is accompanied by partial FMRP reduction. As complete loss of FMRP induces FXS in children, future experiments should aim at evaluation of CMBL4c therapeutic intervention in differentiated tissues, in which FMRpolyG translation inhibition might outweigh adverse effects related to FMRP depletion.Item Partners in crime: proteins implicated in RNA repeat expansion diseases(Wiley, 2022) Baud, Anna; Derbis, Magdalena ; Tutak, Katarzyna ; Sobczak, KrzysztofShort tandem repeats are repetitive nucleotide sequences robustly distributed in the human genome. Their expansion underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X-associated tremor/ ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs). Several molecular pathomechanisms associated with toxic RNA containing expanded repeats (RNAexp) are shared among REDs and contribute to disease progression, however, detailed mechanistic insight into those processes is limited. To deepen our understanding of the interplay between toxic RNAexp molecules and multiple protein partners, in this review, we discuss the roles of selected RNA-binding proteins (RBPs) that interact with RNAexp and thus act as “partners in crime” in the progression of REDs. We gather current findings concerning RBPs involved at different stages of the RNAexp life cycle, such as transcription, splicing, transport, and AUG-independent translation of expanded repeats. We argue that the activity of selected RBPs can be unique or common among REDs depending on the expanded repeat type. We also present proteins that are functionally depleted due to sequestration on RNAexp within nuclear foci and those which participate in RNAexp-dependent innate immunity activation.