Lien vers HAL – pasteur-04315190
Lien DOI – 10.1002/anie.202314587
Angewandte Chemie International Edition, 2024, 63 (3), pp.e202314587. ⟨10.1002/anie.202314587⟩
Preventing the misfolding or aggregation of transactive response DNA binding protein with 43 kDa (TDP‐43) is the most actively pursued disease‐modifying strategy to treat amyotrophic lateral sclerosis and other neurodegenerative diseases. In this work, we provide proof of concept that native state stabilization of TDP‐43 is a viable and effective strategy for treating TDP‐43 proteinopathies. Firstly, we leveraged the Cryo‐EM structures of TDP‐43 fibrils to design C‐terminal substitutions that disrupt TDP‐43 aggregation. Secondly, we showed that these substitutions (S333D/S342D) stabilize monomeric TDP‐43 without altering its physiological properties. Thirdly, we demonstrated that binding native oligonucleotide ligands stabilized monomeric TDP‐43 and prevented its fibrillization and phase separation in the absence of direct binding to the aggregation‐prone C‐terminal domain. Fourthly, we showed that the monomeric TDP‐43 variant could be induced to aggregate in a controlled manner, which enabled the design and implementation of a high‐throughput screening assay to identify native state stabilizers of TDP‐43. Altogether, our findings demonstrate that different structural domains in TDP‐43 could be exploited and targeted to develop drugs that stabilize the native state of TDP‐43 and provide a platform to discover novel drugs to treat TDP‐43 proteinopathies.