14-3-3θ, a novel player in TDP-43 pathophysiology: Implications for ALS/FTD

In this issue of Neuron, Ke et al. 1 Ke Y.D. van Hummel A. Au C. Chan G. Lee W.S. van der Hoven J. Przybyla M. Deng Y. Sabale M. Morey N. et al. Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice. Neuron. 2024; 112: 1249-1264https://doi.org/10.1016/j.neuron.2024.01.022 Abstract Full Text Full Text PDF Scopus (1) Google Scholar report a novel non-canonical interaction between 14-3-3θ and TDP-43 that impacts loss-of-function and gain-of-toxic pathology in TDP-43 proteinopathies. The authors further provide proof of principle for a 14-3-3θ-targeted gene therapy to reduce TDP-43-induced deficits in transgenic TDP-43 mutant mice. In this issue of Neuron, Ke et al. 1 Ke Y.D. van Hummel A. Au C. Chan G. Lee W.S. van der Hoven J. Przybyla M. Deng Y. Sabale M. Morey N. et al. Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice. Neuron. 2024; 112: 1249-1264https://doi.org/10.1016/j.neuron.2024.01.022 Abstract Full Text Full Text PDF Scopus (1) Google Scholar report a novel non-canonical interaction between 14-3-3θ and TDP-43 that impacts loss-of-function and gain-of-toxic pathology in TDP-43 proteinopathies. The authors further provide proof of principle for a 14-3-3θ-targeted gene therapy to reduce TDP-43-induced deficits in transgenic TDP-43 mutant mice. Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia miceKe et al.NeuronFebruary 15, 2024In BriefTDP-43 forms neuronal deposits in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) due to unknown causes. Ke et al. identified the TDP-43 interactor 14-3-3θ, which promotes TDP-43 deposition. They devised a treatment harnessing 14-3-3θ's affinity for TDP-43, mitigating deficits and neurodegeneration in ALS/FTD models with implications for future therapy. Full-Text PDF