Effective Inhibition of TDP-43 Aggregation by Native State Stabilization

Angew Chem Int Ed Engl. 2024 Jan 15;63(3):e202314587. doi: 10.1002/anie.202314587. Epub 2023 Dec 11.

Abstract

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.

Keywords: Aggregation; Native-State Stabilization; Oligonucleotides; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / metabolism
  • DNA-Binding Proteins / chemistry
  • Humans
  • Neurodegenerative Diseases*
  • TDP-43 Proteinopathies* / genetics
  • TDP-43 Proteinopathies* / metabolism

Substances

  • DNA-Binding Proteins