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Fighting the Huntington’s Disease with a G-Quadruplex-Forming Aptamer Specifically Binding to Mutant Huntingtin Protein: Biophysical Characterization, In Vitro and In Vivo Studies
Riccardi, Claudia D'Aria, Federica Digilio, Filomena Anna Carillo, Maria Rosaria Amato, Jussara Fasano, Dominga De Rosa, Laura Paladino, Simona Montesarchio, Daniela
Riccardi, Claudia
D'Aria, Federica
Digilio, Filomena Anna
Carillo, Maria Rosaria
Amato, Jussara
Fasano, Dominga
De Rosa, Laura
Paladino, Simona
Montesarchio, Daniela
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2022-04-27
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http://dx.doi.org/10.3390/ijms23094804
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A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical characterization of the best aptamer in the series, named MS3, proved to adopt a stable, parallel G-quadruplex structure and show high nuclease resistance in serum. Confocal microscopy experiments on HeLa and SH-SY5Y cells, as models of non-neuronal and neuronal cells, respectively, showed a rapid, dose-dependent uptake of fluorescein-labelled MS3, demonstrating its effective internalization, even in the absence of transfecting agents, with no general cytotoxicity. Then, using a well-established Drosophila melanogaster model for Huntington’s disease, which expresses the mutated form of human huntingtin, a significant improvement in the motor neuronal function in flies fed with MS3 was observed, proving the in vivo efficacy of this aptamer.
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Riccardi, C.; D’Aria, F.; Digilio, F.A.; Carillo, M.R.; Amato, J.; Fasano, D.; De Rosa, L.; Paladino, S.; Melone, M.A.B.; Montesarchio, D.; et al. Fighting the Huntington’s Disease with a G-Quadruplex-Forming Aptamer Specifically Binding to Mutant Huntingtin Protein: Biophysical Characterization, In Vitro and In Vivo Studies. Int. J. Mol. Sci. 2022, 23, 4804. https://doi.org/10.3390/ijms23094804
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International Journal of Molecular Sciences, Vol. 23, Iss. 9
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