Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice.

Autor:	Ke YD; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: yazi.ke@mq.edu.au., van Hummel A; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Au C; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Chan G; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Lee WS; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., van der Hoven J; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Przybyla M; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Deng Y; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Sabale M; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Morey N; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Bertz J; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Feiten A; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Ippati S; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Stevens CH; School of Chemistry and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia., Yang S; Centre for MND Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Gladbach A; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Haass NK; The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia., Kril JJ; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia., Blair IP; Centre for MND Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Delerue F; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia., Ittner LM; Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: lars.ittner@mq.edu.au.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Apr 17; Vol. 112 (8), pp. 1249-1264.e8. Date of Electronic Publication: 2024 Feb 15.
DOI:	10.1016/j.neuron.2024.01.022
Abstrakt:	Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy. Competing Interests: Declaration of interests Y.D.K. and L.M.I. are inventors, and A.v.H. and W.S.L. are contributors to patents covering the gene therapy vectors presented here that have been licensed to Celosia Therapeutics (Australia), of which L.M.I. is a co-founder. Celosia Therapeutics was not involved in design, data generation/analysis, or funding of this study. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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