Home > Publications Database > Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding. > print

001     282909
005     20251217171018.0
024 7 _ |a 10.1038/s44318-025-00590-2
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024 7 _ |a 0261-4189
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024 7 _ |a 1460-2075
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037 _ _ |a DZNE-2025-01370
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Simonetti, Francesca
|0 P:(DE-2719)9001596
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245 _ _ |a Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding.
260 _ _ |a [London]
|c 2025
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 7 |a Alzheimer’s Disease
|2 Other
650 _ 7 |a Phase Separation
|2 Other
650 _ 7 |a Seeding
|2 Other
650 _ 7 |a TDP-43
|2 Other
650 _ 7 |a Tau
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650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a DNA-Binding Proteins
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650 _ 7 |a TARDBP protein, human
|2 NLM Chemicals
650 _ 7 |a MAPT protein, human
|2 NLM Chemicals
650 _ 7 |a Protein Aggregates
|2 NLM Chemicals
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
650 _ 2 |a tau Proteins: genetics
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: genetics
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Protein Aggregation, Pathological: metabolism
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Protein Aggregates
|2 MeSH
650 _ 2 |a Protein Binding
|2 MeSH
700 1 _ |a Zhong, Weijia
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700 1 _ |a Hutten, Saskia
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700 1 _ |a Uliana, Federico
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700 1 _ |a Kielisch, Fridolin
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700 1 _ |a Riemenschneider, Henrick
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700 1 _ |a Ruf, Viktoria
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700 1 _ |a Schmidt, Carla
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700 1 _ |a Simons, Mikael
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700 1 _ |a Wegmann, Susanne
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700 1 _ |a Lashley, Tammaryn
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700 1 _ |a Polymenidou, Magdalini
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700 1 _ |a Edbauer, Dieter
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700 1 _ |a Dormann, Dorothee
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773 _ _ |a 10.1038/s44318-025-00590-2
|g Vol. 44, no. 24, p. 7395 - 7433
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