肌萎缩侧索硬化
失智症
神经科学
痴呆
C9orf72
额颞叶变性
医学
病理
心理学
疾病
作者
Yazi D. Ke,Annika van Hummel,Carol G. 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
出处
期刊:Neuron
[Elsevier]
日期:2024-02-01
标识
DOI:10.1016/j.neuron.2024.01.022
摘要
Summary
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.
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