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000282909 1001_ $$0P:(DE-2719)9001596$$aSimonetti, Francesca$$b0$$eFirst author
000282909 245__ $$aDirect interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding.
000282909 260__ $$a[London]$$bNature Publishing Group UK$$c2025
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000282909 520__ $$aNeuronal aggregates of Tau are a hallmark of Alzheimer's disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. Here, we demonstrate that Tau and TDP-43 mutually promote each other's condensation through direct interaction in vitro, forming irregularly-shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau mobility. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with these data, insoluble material extracted from AD patient brains with Tau/TDP-43 co-aggregates exhibits reduced Tau seeding compared to AD patient brains with Tau aggregates only. In contrast, patient-derived extracts from AD patient brains with Tau/TDP-43 co-aggregates are highly potent in seeding new TDP-43 aggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction between TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology in Alzheimer's disease patients.
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000282909 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x1
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000282909 650_7 $$2Other$$aAlzheimer’s Disease
000282909 650_7 $$2Other$$aPhase Separation
000282909 650_7 $$2Other$$aSeeding
000282909 650_7 $$2Other$$aTDP-43
000282909 650_7 $$2Other$$aTau
000282909 650_7 $$2NLM Chemicals$$atau Proteins
000282909 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000282909 650_7 $$2NLM Chemicals$$aTARDBP protein, human
000282909 650_7 $$2NLM Chemicals$$aMAPT protein, human
000282909 650_7 $$2NLM Chemicals$$aProtein Aggregates
000282909 650_2 $$2MeSH$$atau Proteins: metabolism
000282909 650_2 $$2MeSH$$atau Proteins: genetics
000282909 650_2 $$2MeSH$$aHumans
000282909 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000282909 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000282909 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000282909 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000282909 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000282909 650_2 $$2MeSH$$aProtein Aggregation, Pathological: metabolism
000282909 650_2 $$2MeSH$$aBrain: metabolism
000282909 650_2 $$2MeSH$$aBrain: pathology
000282909 650_2 $$2MeSH$$aProtein Aggregates
000282909 650_2 $$2MeSH$$aProtein Binding
000282909 7001_ $$00000-0003-3429-250X$$aZhong, Weijia$$b1
000282909 7001_ $$aHutten, Saskia$$b2
000282909 7001_ $$00000-0002-8185-6438$$aUliana, Federico$$b3
000282909 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b4$$udzne
000282909 7001_ $$0P:(DE-2719)9000720$$aRezaei, Ali$$b5
000282909 7001_ $$0P:(DE-2719)9001275$$aRamirez, Lisa Marie$$b6$$udzne
000282909 7001_ $$0P:(DE-2719)2812812$$aHochmair, Janine$$b7$$udzne
000282909 7001_ $$0P:(DE-2719)9002552$$aSankar, Rithika$$b8$$udzne
000282909 7001_ $$aGopalan, Anusha$$b9
000282909 7001_ $$00000-0003-3573-8067$$aKielisch, Fridolin$$b10
000282909 7001_ $$0P:(DE-2719)2812261$$aRiemenschneider, Henrick$$b11
000282909 7001_ $$aRuf, Viktoria$$b12
000282909 7001_ $$00000-0001-9410-1424$$aSchmidt, Carla$$b13
000282909 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b14$$udzne
000282909 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b15$$udzne
000282909 7001_ $$0P:(DE-2719)2812695$$aWegmann, Susanne$$b16
000282909 7001_ $$00000-0001-7389-0348$$aLashley, Tammaryn$$b17
000282909 7001_ $$00000-0003-1271-9445$$aPolymenidou, Magdalini$$b18
000282909 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b19
000282909 7001_ $$0P:(DE-2719)9000059$$aDormann, Dorothee$$b20
000282909 773__ $$0PERI:(DE-600)1467419-1$$a10.1038/s44318-025-00590-2$$gVol. 44, no. 24, p. 7395 - 7433$$n24$$p7395 - 7433$$tThe EMBO journal$$v44$$x0261-4189$$y2025
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