Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation
Abstract Transactive response DNA-binding Protein 43 (TDP-43) aggregation is a key pathological feature in Amyotrophic Lateral Sclerosis and related neurodegenerative diseases. This study investigates the inhibitory effects of Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, on TD...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-02035-6 |
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| author | Maria Agnese Morando Vito D’Alessandro Angelo Spinello Martina Sollazzo Elisa Monaca Raffaele Sabbatella Maria Concetta Volpe Francesca Gervaso Alessandro Polini Sarah Mizielinska Caterina Alfano |
| author_facet | Maria Agnese Morando Vito D’Alessandro Angelo Spinello Martina Sollazzo Elisa Monaca Raffaele Sabbatella Maria Concetta Volpe Francesca Gervaso Alessandro Polini Sarah Mizielinska Caterina Alfano |
| author_sort | Maria Agnese Morando |
| collection | DOAJ |
| description | Abstract Transactive response DNA-binding Protein 43 (TDP-43) aggregation is a key pathological feature in Amyotrophic Lateral Sclerosis and related neurodegenerative diseases. This study investigates the inhibitory effects of Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, on TDP-43 aggregation. Using a combination of fluorescence assays, NMR spectroscopy, and computational modeling, we demonstrate that Epigallocatechin-3-gallate significantly delays the nucleation phase of TDP-43 aggregation process, thus inhibiting the formation of TDP-43 aggregates in vitro. Additionally, we proved a direct interaction of the compound with the RNA recognition motifs of TDP-43 and modeled the mechanism of interaction. Our findings reveal that EGCG stabilizes the RRM domains, counteracting aggregation by interfering with the early stages of the amyloidogenic pathway. Furthermore, EGCG’s stability under experimental conditions was ensured using reducing agents, highlighting the importance of maintaining its reduced form for reproducible results. These insights underscore the therapeutic potential of EGCG in TDP-43 proteinopathies and provide a foundation for developing targeted treatments for ALS and related disorders. |
| format | Article |
| id | doaj-art-05b2ccb0f93044dbb610b9801e20a0ea |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-05b2ccb0f93044dbb610b9801e20a0ea2025-08-20T02:34:07ZengNature PortfolioScientific Reports2045-23222025-05-0115111410.1038/s41598-025-02035-6Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregationMaria Agnese Morando0Vito D’Alessandro1Angelo Spinello2Martina Sollazzo3Elisa Monaca4Raffaele Sabbatella5Maria Concetta Volpe6Francesca Gervaso7Alessandro Polini8Sarah Mizielinska9Caterina Alfano10Structural Biology and Biophysics Unit, Fondazione Ri.MEDStructural Biology and Biophysics Unit, Fondazione Ri.MEDDepartment of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of PalermoStructural Biology and Biophysics Unit, Fondazione Ri.MEDStructural Biology and Biophysics Unit, Fondazione Ri.MEDStructural Biology and Biophysics Unit, Fondazione Ri.MEDFondazione Ri.MEDCNR Nanotec-Institute of NanotechnologyCNR Nanotec-Institute of NanotechnologyUK Dementia Research Institute at King’s College LondonStructural Biology and Biophysics Unit, Fondazione Ri.MEDAbstract Transactive response DNA-binding Protein 43 (TDP-43) aggregation is a key pathological feature in Amyotrophic Lateral Sclerosis and related neurodegenerative diseases. This study investigates the inhibitory effects of Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, on TDP-43 aggregation. Using a combination of fluorescence assays, NMR spectroscopy, and computational modeling, we demonstrate that Epigallocatechin-3-gallate significantly delays the nucleation phase of TDP-43 aggregation process, thus inhibiting the formation of TDP-43 aggregates in vitro. Additionally, we proved a direct interaction of the compound with the RNA recognition motifs of TDP-43 and modeled the mechanism of interaction. Our findings reveal that EGCG stabilizes the RRM domains, counteracting aggregation by interfering with the early stages of the amyloidogenic pathway. Furthermore, EGCG’s stability under experimental conditions was ensured using reducing agents, highlighting the importance of maintaining its reduced form for reproducible results. These insights underscore the therapeutic potential of EGCG in TDP-43 proteinopathies and provide a foundation for developing targeted treatments for ALS and related disorders.https://doi.org/10.1038/s41598-025-02035-6EGCG stabilityTDP-43ALSProtein aggregationRNA-binding proteinsProtein-ligand interaction |
| spellingShingle | Maria Agnese Morando Vito D’Alessandro Angelo Spinello Martina Sollazzo Elisa Monaca Raffaele Sabbatella Maria Concetta Volpe Francesca Gervaso Alessandro Polini Sarah Mizielinska Caterina Alfano Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation Scientific Reports EGCG stability TDP-43 ALS Protein aggregation RNA-binding proteins Protein-ligand interaction |
| title | Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation |
| title_full | Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation |
| title_fullStr | Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation |
| title_full_unstemmed | Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation |
| title_short | Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation |
| title_sort | epigallocatechin 3 gallate binds tandem rna recognition motifs of tdp 43 and inhibits its aggregation |
| topic | EGCG stability TDP-43 ALS Protein aggregation RNA-binding proteins Protein-ligand interaction |
| url | https://doi.org/10.1038/s41598-025-02035-6 |
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