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

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. Copyright © 2024 Elsevier Inc. All rights reserved.

Citation

Yazi D Ke, Annika van Hummel, Carol Au, Gabriella Chan, Wei Siang Lee, Julia van der Hoven, Magdalena Przybyla, Yuanyuan Deng, Miheer Sabale, Nicolle Morey, Josefine Bertz, Astrid Feiten, Stefania Ippati, Claire H Stevens, Shu Yang, Amadeus Gladbach, Nikolas K Haass, Jillian J Kril, Ian P Blair, Fabien Delerue, Lars M Ittner. Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice. Neuron. 2024 Apr 17;112(8):1249-1264.e8

Mesh Tags

Substances

PMID: 38366598

search → result