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Small Molecule Screening Discovers Compounds that Reduce FMRpolyG Protein Aggregates and Splicing Defect Toxicity in Fragile X-Associated Tremor/Ataxia Syndrome

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Abstract

Expansion of CGG trinucleotide repeats in 5′ untranslated region of the FMR1 gene is the causative mutation of neurological diseases such as fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and ovarian disorder such as fragile X-associated primary ovarian insufficiency (FXPOI). CGG repeats containing FMR1 transcripts form the toxic ribonuclear aggregates, abrupt pre-mRNA splicing, and cause repeat-associated non-AUG translation, leading to the disease symptoms. Here, we utilized a small molecule library of ~ 250,000 members obtained from the National Cancer Institute (NCI) and implemented a shape-based screening approach to identify the candidate small molecules that mitigate toxic CGG RNA-mediated pathogenesis. The compounds obtained from screening were further assessed for their affinity and selectivity towards toxic CGG repeat RNA by employing fluorescence-binding experiment and isothermal calorimetry titration assay. Three candidate molecules B1, B4, and B11 showed high affinity and selectivity for expanded CGG repeats RNA. Further, NMR spectroscopy, gel mobility shift assay, CD spectroscopy, UV–thermal denaturation assay, and molecular docking affirmed their high affinity and selectivity for toxic CGG RNAs. Next, these lead compounds selectively improved the pre-mRNA alternative splicing defects with no perturbation in global splicing efficacy and simultaneously reduced the FMR1polyG protein aggregate formation without affecting the downstream expression of the gene. Taken together these findings, we addressed compound B1, B4, and B11 as potential lead molecules for develo** promising therapeutics against FXTAS. Herein, this study, we have utilized shape similarity approach to screen the NCI library and found out the potential candidate which improves the pre-mRNA splicing defects and reduces FMR1polyG aggregations.

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Acknowledgements

The authors are grateful to the Sophisticated Instrumentation Facility at IIT Indore for NMR and CD experiments. We sincerely thank Nicolas Charlet Berguerand (Department of Translational Medicine, IGBMC, Illkirch 67400, France) for providing pcDNA3 (CGG)20x, pcDNA3 (CGG)40x, pcDNA3 (CGG)60x, 5′UTR FMR1 (CGG)99x-EGFP, SMN2, Bcl-x, and cTNT minigenes.

Funding

This work was supported and funding provided by the [DST/FT/LS29/2012] Government of India. AKV and EK are thankful to DBT, New Delhi, and SKM thankful to CSIR, New Delhi, for fellowship.

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  1. Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India

    Arun Kumar Verma, Eshan Khan, Subodh Kumar Mishra & Amit Kumar

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AK conceptualized the idea. AK and AKV designed the experiments. Biophysical and cell-based experiments were performed by AV. EK and SKM performed the shape-based molecule screening and helped in experiments. AKV and AK analyzed the data and wrote the manuscript. AK, EK, and SKM edited and also improved the manuscript.

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Correspondence to Amit Kumar.

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Verma, A.K., Khan, E., Mishra, S.K. et al. Small Molecule Screening Discovers Compounds that Reduce FMRpolyG Protein Aggregates and Splicing Defect Toxicity in Fragile X-Associated Tremor/Ataxia Syndrome. Mol Neurobiol 59, 1992–2007 (2022). https://doi.org/10.1007/s12035-021-02697-z

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