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

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 represents an important therapeutic pathway that is worth explorin...

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Autores principales:	Lucia Cragnaz, Greta Spinelli, Laura De Conti, Emilie A. Bureau, Janet Brownlees, Fabian Feiguin, Valentina Romano, Natasa Skoko, Raffaella Klima, Catherine A. Kettleborough, Francisco E. Baralle, Marco Baralle
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	ALS Aggregation Drosophila TBPH TDP-43 Thioridazine Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/4a24bd0945294ac9878244f90dbac4df
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spelling	oai:doaj.org-article:4a24bd0945294ac9878244f90dbac4df2021-11-12T04:25:50ZThioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance1095-953X10.1016/j.nbd.2021.105515https://doaj.org/article/4a24bd0945294ac9878244f90dbac4df2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002643https://doaj.org/toc/1095-953XBrain 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 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 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.Lucia CragnazGreta SpinelliLaura De ContiEmilie A. BureauJanet BrownleesFabian FeiguinValentina RomanoNatasa SkokoRaffaella KlimaCatherine A. KettleboroughFrancisco E. BaralleMarco BaralleElsevierarticleALSAggregationDrosophilaTBPHTDP-43ThioridazineNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 160, Iss , Pp 105515- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ALS Aggregation Drosophila TBPH TDP-43 Thioridazine Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	ALS Aggregation Drosophila TBPH TDP-43 Thioridazine Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Lucia Cragnaz Greta Spinelli Laura De Conti Emilie A. Bureau Janet Brownlees Fabian Feiguin Valentina Romano Natasa Skoko Raffaella Klima Catherine A. Kettleborough Francisco E. Baralle Marco Baralle Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance
description	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 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 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.
format	article
author	Lucia Cragnaz Greta Spinelli Laura De Conti Emilie A. Bureau Janet Brownlees Fabian Feiguin Valentina Romano Natasa Skoko Raffaella Klima Catherine A. Kettleborough Francisco E. Baralle Marco Baralle
author_facet	Lucia Cragnaz Greta Spinelli Laura De Conti Emilie A. Bureau Janet Brownlees Fabian Feiguin Valentina Romano Natasa Skoko Raffaella Klima Catherine A. Kettleborough Francisco E. Baralle Marco Baralle
author_sort	Lucia Cragnaz
title	Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance
title_short	Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance
title_full	Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance
title_fullStr	Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance
title_full_unstemmed	Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance
title_sort	thioridazine reverts the phenotype in cellular and drosophila models of amyotrophic lateral sclerosis by enhancing tdp-43 aggregate clearance
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/4a24bd0945294ac9878244f90dbac4df
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Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance

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