%0 Journal Article
%A Simonetti, Francesca
%A Zhong, Weijia
%A Hutten, Saskia
%A Uliana, Federico
%A Schifferer, Martina
%A Rezaei, Ali
%A Ramirez, Lisa Marie
%A Hochmair, Janine
%A Sankar, Rithika
%A Gopalan, Anusha
%A Kielisch, Fridolin
%A Riemenschneider, Henrick
%A Ruf, Viktoria
%A Schmidt, Carla
%A Simons, Mikael
%A Zweckstetter, Markus
%A Wegmann, Susanne
%A Lashley, Tammaryn
%A Polymenidou, Magdalini
%A Edbauer, Dieter
%A Dormann, Dorothee
%T Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding.
%J The EMBO journal
%V 44
%N 24
%@ 0261-4189
%C [London]
%I Nature Publishing Group UK
%M DZNE-2025-01370
%P 7395 - 7433
%D 2025
%X Neuronal aggregates of Tau are a hallmark of Alzheimer's disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. Here, we demonstrate that Tau and TDP-43 mutually promote each other's condensation through direct interaction in vitro, forming irregularly-shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau mobility. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with these data, insoluble material extracted from AD patient brains with Tau/TDP-43 co-aggregates exhibits reduced Tau seeding compared to AD patient brains with Tau aggregates only. In contrast, patient-derived extracts from AD patient brains with Tau/TDP-43 co-aggregates are highly potent in seeding new TDP-43 aggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction between TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology in Alzheimer's disease patients.
%K tau Proteins: metabolism
%K tau Proteins: genetics
%K Humans
%K DNA-Binding Proteins: metabolism
%K DNA-Binding Proteins: genetics
%K Alzheimer Disease: metabolism
%K Alzheimer Disease: pathology
%K Alzheimer Disease: genetics
%K Protein Aggregation, Pathological: metabolism
%K Brain: metabolism
%K Brain: pathology
%K Protein Aggregates
%K Protein Binding
%K Alzheimer’s Disease (Other)
%K Phase Separation (Other)
%K Seeding (Other)
%K TDP-43 (Other)
%K Tau (Other)
%K tau Proteins (NLM Chemicals)
%K DNA-Binding Proteins (NLM Chemicals)
%K TARDBP protein, human (NLM Chemicals)
%K MAPT protein, human (NLM Chemicals)
%K Protein Aggregates (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41107545
%R 10.1038/s44318-025-00590-2
%U https://pub.dzne.de/record/282909