Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation

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

doi:10.1038/s41598-025-02035-6

Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation

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

Basic and Clinical Neuroscience

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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.

Original language	English
Article number	17879
Pages (from-to)	17879
Journal	Scientific Reports
Volume	15
Issue number	1
Early online date	23 May 2025
DOIs	https://doi.org/10.1038/s41598-025-02035-6
Publication status	E-pub ahead of print - 23 May 2025

Keywords

Catechin/analogs & derivatives
DNA-Binding Proteins/metabolism
Humans
Protein Binding
Protein Aggregates/drug effects
RNA Recognition Motif
Amyotrophic Lateral Sclerosis/metabolism

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Epigallocatechin-3-gallate binds_MORANDO_Publishedonline23May2025_GOLD_VoR (CC BY)Final published version, 6.1 MBLicence: CC BY

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Morando, M. A., D'Alessandro, V., Spinello, A., Sollazzo, M., Monaca, E., Sabbatella, R., Volpe, M. C., Gervaso, F., Polini, A., Mizielinska, S., & Alfano, C. (2025). Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation. Scientific Reports, 15(1), 17879. Article 17879. Advance online publication. https://doi.org/10.1038/s41598-025-02035-6

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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.",

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AU - Morando, Maria Agnese

AU - D'Alessandro, Vito

AU - Spinello, Angelo

AU - Sollazzo, Martina

AU - Monaca, Elisa

AU - Sabbatella, Raffaele

AU - Volpe, Maria Concetta

AU - Gervaso, Francesca

AU - Polini, Alessandro

AU - Mizielinska, Sarah

AU - Alfano, Caterina

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PY - 2025/5/23

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Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation

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