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| Home > Publications Database > Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding. |
| Home > Publications Database > Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding. |
| Journal Article | DZNE-2025-01370 |
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2025
Nature Publishing Group UK
[London]
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Please use a persistent id in citations: doi:10.1038/s44318-025-00590-2
Abstract: 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.
Keyword(s): tau Proteins: metabolism (MeSH) ; tau Proteins: genetics (MeSH) ; Humans (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Protein Aggregates (MeSH) ; Protein Binding (MeSH) ; Alzheimer’s Disease ; Phase Separation ; Seeding ; TDP-43 ; Tau ; tau Proteins ; DNA-Binding Proteins ; TARDBP protein, human ; MAPT protein, human ; Protein Aggregates
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