Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance

Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance

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Brain inclusions mainly composed of misfolded and aggregated TAR DNA binding protein 43 (TDP-43), are characteristic hallmarks of amyotrophic lateral sclerosis (ALS).Irrespective of the role played by the inclusions, their reduction Soccer - Shoes Outdoor - Junior represents an important therapeutic pathway that is worth exploring.Their removal can either lead to the recovery of TDP-43 function by removing the self-templating conformers that sequester the protein in the inclusions, and/or eliminate any potential intrinsic toxicity of the aggregates.The search for curative therapies has been hampered by the lack of ALS models for use in high-throughput screening.We adapted, optimised, and extensively characterised our previous ALS cellular model for such use.

The model demonstrated efficient aggregation of endogenous TDP-43, and concomitant loss of its splicing regulation function.We provided a proof-of-principle for its eventual use in high-throughput screening using compounds of the tricyclic family and showed that recovery of TDP-43 function can be achieved by the enhanced removal of TDP-43 aggregates by these compounds.We observed that the degradation of the aggregates occurs independent of the autophagy pathway beyond autophagosome-lysosome fusion, but requires a TARGETS functional proteasome pathway.The in vivo translational effect of the cellular model was tested with two of these compounds in a Drosophila model expressing a construct analogous to the cellular model, where thioridazine significantly improved the locomotive defect.Our findings have important implications as thioridazine cleared TDP-43 aggregates and recovered TDP-43 functionality.

This study also highlights the importance of a two-stage, in vitro and in vivo model system to cross-check the search for small molecules that can clear TDP-43 aggregates in TDP-43 proteinopathies.