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Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding

Simonetti, Francesca, Zhong, Weijia, Hutten, Saskia, Uliana, Federico, Schifferer, Martina, Rezaei, Ali, Ramirez, Lisa Marie, Hochmair, Janine, Sankar, Rithika, Gopalan, Anusha, Kielisch, Fridolin, Riemenschneider, Henrick, Ruf, Viktoria, Schmidt, Carla, Simons, Mikael, Zweckstetter, Markus, Wegmann, Susanne, Lashley, Tammaryn, Polymenidou, Magdalini, Edbauer, Dieter, Dormann, Dorothee·2025·The EMBO Journal
DOI 10.1038/s44318-025-00590-2PMC PMC12706024
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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.

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Figure 1 Tau, but not MBP or α-synuclein, causes formation of large irregular TDP-43 condensates. (A) Scheme of TDP-43 phase separation assay upon TEV-cleavage of the MBP-solubility tag; created with BioRender.com. (B) Time series of Alexa488-labeled TDP-43 condensate formation (8 µM) in presence or absence of DyLight650-labeled Tau (8 µM), from 20 to 45 min after cleavage with TEV protease; images represent frames of Movies EV1 and EV2; scale bar: 10 µm. (C) Confocal images of Alexa488-labeled TDP-43 condensates (5 µM) in presence of unlabeled Tau, MBP, or α-synuclein (2, 5 or 10 µM), 30 min after TEV-cleavage. Scale bar: 15 µm in overview and 8 µm in inset. (D) Graphs showing number of particles, circularity, and size of the TDP-43 condensates. Individual data points from (n = 2) biological replicates are shown. (E) Representative FRAP images of Alexa488-labeled TDP-43 condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled Tau, MBP, or α-synuclein, within 15 min of TEV protease addition. Dotted box indicates the bleached area (half of the condensate). Scale bar: 1 µm. (F) FRAP recovery curves following half-bleaching of Alexa488-labeled TDP-43 condensates in absence or presence of Tau, MBP, and α-synuclein. Data represent ± SEM from 11 to 12 individual condensates analyzed per condition in four biological replicates. ***P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition; significant difference was determined by calculating the area under the curve (AUC) for each condition.
Figure 1 Tau, but not MBP or α-synuclein, causes formation of large irregular TDP-43 condensates. (A) Scheme of TDP-43 phase separation assay upon TEV-cleavage of the MBP-solubility tag; created with BioRender.com. (B) Time series of Alexa488-labeled TDP-43 condensate formation (8 µM) in presence or absence of DyLight650-labeled Tau (8 µM), from 20 to 45 min after cleavage with TEV protease; images represent frames of Movies EV1 and EV2; scale bar: 10 µm. (C) Confocal images of Alexa488-labeled TDP-43 condensates (5 µM) in presence of unlabeled Tau, MBP, or α-synuclein (2, 5 or 10 µM), 30 min after TEV-cleavage. Scale bar: 15 µm in overview and 8 µm in inset. (D) Graphs showing number of particles, circularity, and size of the TDP-43 condensates. Individual data points from (n = 2) biological replicates are shown. (E) Representative FRAP images of Alexa488-labeled TDP-43 condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled Tau, MBP, or α-synuclein, within 15 min of TEV protease addition. Dotted box indicates the bleached area (half of the condensate). Scale bar: 1 µm. (F) FRAP recovery curves following half-bleaching of Alexa488-labeled TDP-43 condensates in absence or presence of Tau, MBP, and α-synuclein. Data represent ± SEM from 11 to 12 individual condensates analyzed per condition in four biological replicates. ***P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition; significant difference was determined by calculating the area under the curve (AUC) for each condition.CC BY · PubMed Central
Figure EV1 pTau, but not the Tau N-terminal domain or repeat domain, enriches in TDP-43 condensates and aggregates. (A) Scheme of recombinant Tau variants with their respective net charges; created with BioRender.com. (B) Coomassie-stained SDS-PAGE gel showing the molecular sizes of Tau, phosphorylated Tau (pTau), Tau N-terminal domain (Tau-NTD), and the Tau-RD fragment (R1–R4 repeat domains). (C) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in a phase separation assay. Scale bar: 15 µm in overview and 3 µm in inset. (D) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 condensates quantified by measuring the area of condensates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM. (E) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in an aggregation assay. Scale bar: 15 µm in overview and 3 µm in inset. (F) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 aggregates quantified by measuring the area of aggregates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM.
Figure EV1 pTau, but not the Tau N-terminal domain or repeat domain, enriches in TDP-43 condensates and aggregates. (A) Scheme of recombinant Tau variants with their respective net charges; created with BioRender.com. (B) Coomassie-stained SDS-PAGE gel showing the molecular sizes of Tau, phosphorylated Tau (pTau), Tau N-terminal domain (Tau-NTD), and the Tau-RD fragment (R1–R4 repeat domains). (C) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in a phase separation assay. Scale bar: 15 µm in overview and 3 µm in inset. (D) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 condensates quantified by measuring the area of condensates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM. (E) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in an aggregation assay. Scale bar: 15 µm in overview and 3 µm in inset. (F) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 aggregates quantified by measuring the area of aggregates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM.CC BY · PubMed Central
Figure 2 TDP-43 and Tau directly interact in condensates formed in vitro. (A) Scheme of XL-MS experiment; created with BioRender.com. (B) Inter-protein crosslinked peptides identified for TDP-43 + Tau and TDP-43 + MBP under bulk and pellet conditions following condensate induction (n = 3) independent replicates. Only crosslinks detected in at least two out of three replicates, with a peptide-spectrum match (PSM) false discovery rate (FDR) < 1% from light and heavy isotope-labeled DSS crosslinking experiments, were included. Inter-protein crosslinks are shown in grey, with line thickness proportional to the spectral count (i.e., relative abundance).
Figure 2 TDP-43 and Tau directly interact in condensates formed in vitro. (A) Scheme of XL-MS experiment; created with BioRender.com. (B) Inter-protein crosslinked peptides identified for TDP-43 + Tau and TDP-43 + MBP under bulk and pellet conditions following condensate induction (n = 3) independent replicates. Only crosslinks detected in at least two out of three replicates, with a peptide-spectrum match (PSM) false discovery rate (FDR) < 1% from light and heavy isotope-labeled DSS crosslinking experiments, were included. Inter-protein crosslinks are shown in grey, with line thickness proportional to the spectral count (i.e., relative abundance).CC BY · PubMed Central
Figure 3 Tau, but not MBP or α-synuclein, promotes TDP-43 aggregation. (A) Scheme of TDP-43 aggregation assay for SDD-AGE experiment; created with BioRender.com. (B) SDD-AGE of TDP-43-MBP (2 µM) in the presence of the indicated protein (2 µM) after agitation and incubation for the presented time period (h = hours, d = days); TDP-43 was visualized by immunoblotting and the middle vertical black line divides two blots which derive from the same experiment and were processed in parallel. °°° = high molecular weight (HMW) species, °° = oligomers and ° = monomers. (C) Quantification of band intensities of the high molecular weight species from (n = 3) biological replicates, normalized to the timepoint 0; values show the mean ± SEM; **P = 0.0039 and *P = 0.0273 by two-way ANOVA with Dunnett´s multiple comparison test to TDP-43-MBP only condition at the respective time points (0, 1 h, 2 h, 8 h, 1 d, 2 d, 6 d). (D) Scheme of Alexa488-labeled TDP-43 aggregation for confocal imaging; created with BioRender.com. (E) Confocal images of Alexa488-labeled TDP-43 aggregates (10 µM) in presence of unlabeled Tau, MBP or α-synuclein (5, 10 or 20 µM) 2 h after the agitation step. Scale bar: 20 µm in overview and 15 µm in inset. (F) Quantification of the total area covered by the TDP-43 aggregates (Aggr. area). Bar graph shows the mean of (n = 4) biological replicates ± SD. ***P = 0.0008 and *P = 0.0255 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition.
Figure 3 Tau, but not MBP or α-synuclein, promotes TDP-43 aggregation. (A) Scheme of TDP-43 aggregation assay for SDD-AGE experiment; created with BioRender.com. (B) SDD-AGE of TDP-43-MBP (2 µM) in the presence of the indicated protein (2 µM) after agitation and incubation for the presented time period (h = hours, d = days); TDP-43 was visualized by immunoblotting and the middle vertical black line divides two blots which derive from the same experiment and were processed in parallel. °°° = high molecular weight (HMW) species, °° = oligomers and ° = monomers. (C) Quantification of band intensities of the high molecular weight species from (n = 3) biological replicates, normalized to the timepoint 0; values show the mean ± SEM; **P = 0.0039 and *P = 0.0273 by two-way ANOVA with Dunnett´s multiple comparison test to TDP-43-MBP only condition at the respective time points (0, 1 h, 2 h, 8 h, 1 d, 2 d, 6 d). (D) Scheme of Alexa488-labeled TDP-43 aggregation for confocal imaging; created with BioRender.com. (E) Confocal images of Alexa488-labeled TDP-43 aggregates (10 µM) in presence of unlabeled Tau, MBP or α-synuclein (5, 10 or 20 µM) 2 h after the agitation step. Scale bar: 20 µm in overview and 15 µm in inset. (F) Quantification of the total area covered by the TDP-43 aggregates (Aggr. area). Bar graph shows the mean of (n = 4) biological replicates ± SD. ***P = 0.0008 and *P = 0.0255 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition.CC BY · PubMed Central
Figure 4 TDP-43-MBP, but not MBP or α-synuclein, causes the formation of large, amorphous Tau condensates in vitro. (A) Schematic representation of Tau phase separation assay; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau only, Alexa633-labeled TDP-43-MBP only, and DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-MBP, DyLight650-labeled MBP or Lumidyne650-labeled α-synuclein at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 5 µm in inset. Images shown are representative images from one experiment out of 6 experimental replicates, all of which yielded similar results. (C) Representative FRAP images of DyLight488-labeled Tau condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled TDP-43-MBP, MBP, or α-synuclein, within 1.5 h of 10% PEG addition. Dotted circle indicates the bleached area (point bleach). Scale bar: 1 µm. (D) Parameters of exponential recovery models fitted to FRAP curves of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Error bars represent 95% confidence intervals based on 14–16 curves per condition, collected across four biological replicates. The center of error bars represents the estimated values. **P = 0.001744 and ****P = 2e-20 by t tests of regression parameters (Wald-type tests). (E) FRAP curves following point-bleaching of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Points and error bars represent mean ± SEM from 14 to 16 individual condensates per condition, collected across four biological replicates. Solid lines show exponential recovery model fits used for statistical analysis in (D).
Figure 4 TDP-43-MBP, but not MBP or α-synuclein, causes the formation of large, amorphous Tau condensates in vitro. (A) Schematic representation of Tau phase separation assay; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau only, Alexa633-labeled TDP-43-MBP only, and DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-MBP, DyLight650-labeled MBP or Lumidyne650-labeled α-synuclein at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 5 µm in inset. Images shown are representative images from one experiment out of 6 experimental replicates, all of which yielded similar results. (C) Representative FRAP images of DyLight488-labeled Tau condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled TDP-43-MBP, MBP, or α-synuclein, within 1.5 h of 10% PEG addition. Dotted circle indicates the bleached area (point bleach). Scale bar: 1 µm. (D) Parameters of exponential recovery models fitted to FRAP curves of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Error bars represent 95% confidence intervals based on 14–16 curves per condition, collected across four biological replicates. The center of error bars represents the estimated values. **P = 0.001744 and ****P = 2e-20 by t tests of regression parameters (Wald-type tests). (E) FRAP curves following point-bleaching of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Points and error bars represent mean ± SEM from 14 to 16 individual condensates per condition, collected across four biological replicates. Solid lines show exponential recovery model fits used for statistical analysis in (D).CC BY · PubMed Central
Figure EV2 Early intra-droplet structures appear at the initial stages of multiphasic Tau/TDP-43 co-condensate formation. (A–C) High resolution images using AiryScan of 1:1 DyLight488-labeled Tau with Alexa633-labeled TDP-43-MBP mixed condensates after 10 min (A), 2 h (B) or (C) 24 h incubation. Scale bar: 1 μm (A), 2 µm (B) or 10 µm (C). In (A), dotted lines show the origin of line profiles indicated on the right, demonstrating demixing of Tau and TDP-43 within the same condensate at early timepoints.
Figure EV2 Early intra-droplet structures appear at the initial stages of multiphasic Tau/TDP-43 co-condensate formation. (A–C) High resolution images using AiryScan of 1:1 DyLight488-labeled Tau with Alexa633-labeled TDP-43-MBP mixed condensates after 10 min (A), 2 h (B) or (C) 24 h incubation. Scale bar: 1 μm (A), 2 µm (B) or 10 µm (C). In (A), dotted lines show the origin of line profiles indicated on the right, demonstrating demixing of Tau and TDP-43 within the same condensate at early timepoints.CC BY · PubMed Central
Figure EV3 Distinct regions of TDP-43 contribute to Tau phase separation and the formation of multiphasic co-condensates. (A) Scheme of recombinant TDP-43 deletion mutants; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-WT-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, TDP-43-RRM, TDP-43-Δ1-101-MBP, or TDP-43-ΔCR-MBP at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 2 µm in inset.
Figure EV3 Distinct regions of TDP-43 contribute to Tau phase separation and the formation of multiphasic co-condensates. (A) Scheme of recombinant TDP-43 deletion mutants; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-WT-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, TDP-43-RRM, TDP-43-Δ1-101-MBP, or TDP-43-ΔCR-MBP at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 2 µm in inset.CC BY · PubMed Central
Figure 5 TDP-43 inhibits Tau fibrillization and promotes formation of small, oligomeric Tau and Tau/TDP-43 assemblies. (A) Schemes of Thioflavin T (ThT) and Tau fibrillization assays; created with BioRender.com. (B) Graph showing normalized ThT fluorescence measurements over 18 h ± SEM in (n > 3) biological replicates. *P = 0.0184 was determined by one-way ANOVA with Dunnett’s multiple comparison test, comparing each condition to Tau ΔK280 inly condition; significant difference was determined by calculating the area under the curve (AUC) for each condition. (C) TEM images of Tau, TDP-43-MBP, MBP or α-synuclein only (50 µM), and Tau in presence of TDP-43-MBP, MBP or α-synuclein, respectively, at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for Tau+TDP-43-MBP and TDP-43-MBP only, and 0.5 µm for Tau only, Tau+MBP, MBP only, Tau+α-synuclein and α-synuclein only. (D) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (E) Quantification of the number of structures positive for either Tau antibody (Tau mAB, small black circle), TDP-43 antibody (TDP-43 mAB, large black circle), or both, quantified for Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only conditions, following double gold immunostaining. Bar graph depict final values obtained by subtracting the number of positive structures observed in control samples stained with secondary antibodies only (see Appendix Fig. S6). Values were analyzed in n > 21 technical experiments. Scale bar: 0.1 µm and 0.03 µm in inset. (F) Representative images of Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only stained with both Tau mAB and TDP-43 mAB.
Figure 5 TDP-43 inhibits Tau fibrillization and promotes formation of small, oligomeric Tau and Tau/TDP-43 assemblies. (A) Schemes of Thioflavin T (ThT) and Tau fibrillization assays; created with BioRender.com. (B) Graph showing normalized ThT fluorescence measurements over 18 h ± SEM in (n > 3) biological replicates. *P = 0.0184 was determined by one-way ANOVA with Dunnett’s multiple comparison test, comparing each condition to Tau ΔK280 inly condition; significant difference was determined by calculating the area under the curve (AUC) for each condition. (C) TEM images of Tau, TDP-43-MBP, MBP or α-synuclein only (50 µM), and Tau in presence of TDP-43-MBP, MBP or α-synuclein, respectively, at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for Tau+TDP-43-MBP and TDP-43-MBP only, and 0.5 µm for Tau only, Tau+MBP, MBP only, Tau+α-synuclein and α-synuclein only. (D) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (E) Quantification of the number of structures positive for either Tau antibody (Tau mAB, small black circle), TDP-43 antibody (TDP-43 mAB, large black circle), or both, quantified for Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only conditions, following double gold immunostaining. Bar graph depict final values obtained by subtracting the number of positive structures observed in control samples stained with secondary antibodies only (see Appendix Fig. S6). Values were analyzed in n > 21 technical experiments. Scale bar: 0.1 µm and 0.03 µm in inset. (F) Representative images of Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only stained with both Tau mAB and TDP-43 mAB.CC BY · PubMed Central
Figure 6 TDP-43 inhibits Tau fibrillization via its N-Terminal fragment and suppresses Tau seeding in a Tau biosensor cells. (A) TEM images of Tau, TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP only (50 µM), and Tau in presence of TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for TDP-43-MBP only, TDP-43-NTF-MBP only, TDP-43-CTF-MBP only, and Tau+TDP-43-CTF-MBP; 0.2 µm for Tau+TDP-43-MBP and Tau+TDP-43-NTF-MBP; 0.5 µm for Tau only. (B) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (C) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using in vitro generated Tau assemblies as seeds; created with BioRender.com. (D) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding Tau biosensor cells with 5 days old recombinant Tau aggregates +/− TDP-43-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, MBP and α-synuclein. The ‘No seeds’ condition refers to cells treated with lipofectamine only. Scale bar: 70 µm in overview and 20 µm in inset. (E) Quantification of number of aggregates per cell. Bar graphs show the number of biological replicates ± SEM in (n = 5) biological replicates (different batches of cells on different days). *P = 0.0274 by one-way ANOVA Kruskal–Wallis test with Dunn´s multiple comparison test to Tau only condition.
Figure 6 TDP-43 inhibits Tau fibrillization via its N-Terminal fragment and suppresses Tau seeding in a Tau biosensor cells. (A) TEM images of Tau, TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP only (50 µM), and Tau in presence of TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for TDP-43-MBP only, TDP-43-NTF-MBP only, TDP-43-CTF-MBP only, and Tau+TDP-43-CTF-MBP; 0.2 µm for Tau+TDP-43-MBP and Tau+TDP-43-NTF-MBP; 0.5 µm for Tau only. (B) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (C) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using in vitro generated Tau assemblies as seeds; created with BioRender.com. (D) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding Tau biosensor cells with 5 days old recombinant Tau aggregates +/− TDP-43-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, MBP and α-synuclein. The ‘No seeds’ condition refers to cells treated with lipofectamine only. Scale bar: 70 µm in overview and 20 µm in inset. (E) Quantification of number of aggregates per cell. Bar graphs show the number of biological replicates ± SEM in (n = 5) biological replicates (different batches of cells on different days). *P = 0.0274 by one-way ANOVA Kruskal–Wallis test with Dunn´s multiple comparison test to Tau only condition.CC BY · PubMed Central
Figure EV4 Western blot characterization of SarkoSpin extracts from human patients. (A) anti-Tau antibody; (B) Anti-phospho-TDP-43 (S409/410) antibody; (C) Anti-TDP-43 antibody; (D) Anti-α-synuclein antibody. Western blots of SarkoSpin fractions derived from the frontal cortex of non-ND, AD + , AD–, FTLD-TDP, and FTLD-Tau patients, and from the cingulate cortex of PD patients, probed with the indicated antibodies. Dashed lines indicate divisions within the same blot.
Figure EV4 Western blot characterization of SarkoSpin extracts from human patients. (A) anti-Tau antibody; (B) Anti-phospho-TDP-43 (S409/410) antibody; (C) Anti-TDP-43 antibody; (D) Anti-α-synuclein antibody. Western blots of SarkoSpin fractions derived from the frontal cortex of non-ND, AD + , AD–, FTLD-TDP, and FTLD-Tau patients, and from the cingulate cortex of PD patients, probed with the indicated antibodies. Dashed lines indicate divisions within the same blot.CC BY · PubMed Central
Figure EV5 Characterization of patient-derived SarkoSpin extracts by immunohistochemistry and dual immunofluorescence. (A, B) Immunohistochemical images of representative non-ND and AD+ brain sections stained with antibodies against phosphorylated Tau (AT8) and TDP-43 in either the hippocampus or frontal cortex. Scale bar: 50 μm. (C) Double fluorescence immunostaining of two representative AD+ cases showing phosphorylated Tau (AT8, green) and TDP-43 (red) in the hippocampus. Scale bar: 30 μm.
Figure EV5 Characterization of patient-derived SarkoSpin extracts by immunohistochemistry and dual immunofluorescence. (A, B) Immunohistochemical images of representative non-ND and AD+ brain sections stained with antibodies against phosphorylated Tau (AT8) and TDP-43 in either the hippocampus or frontal cortex. Scale bar: 50 μm. (C) Double fluorescence immunostaining of two representative AD+ cases showing phosphorylated Tau (AT8, green) and TDP-43 (red) in the hippocampus. Scale bar: 30 μm.CC BY · PubMed Central
Figure 7 Sarkospin extracts from AD patients with Tau/TDP-43 co-pathology (AD+) show a lower Tau seeding potency compared to AD patients with Tau-only pathology (AD−) and contain TDP-43 seeding competent species. (A) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using SarkoSpin patient extracts as seeds; created with BioRender.com. (B) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding the cells with non-ND 1, FTLD-Tau 2, AD − 2, AD + 2, FTLD-TDP 5, or PD 2 SarkoSpin extracts. Scale bar: 70 µm in overview and 15 µm in inset. (C) Quantification of number and area of aggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. ****P < 0.0001, **P = 0.0030, and *P = 0.0317 (number of aggregates), and ****P < 0.0001, **P = 0.0033, and *P = 0.0173 (area of aggregates) by one-way ANOVA with Šídák´s multiple comparison test to non-ND. (D) Scheme of TDP-43 seeding assay using doxycycline-inducible TDP-43-HA HEK293 cells; created with BioRender.com. (E) Representative confocal images of cytosolic pS409/410-positive TDP-43 neoaggregates in HEK293 cells, after transfection with non-ND 1, FTLD-TDP 5, AD + 2, AD − 2, FTLD-Tau 2, or PD 2 SarkoSpin patient extracts. DAPI is depicted in blue, HA staining in green, and pS409/410 in magenta. Scale bar: 50 µm in overview and 10 µm in inset. (F) Quantification of HA and pS409/410-TDP-43 colocalization as number and area of neoaggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. **P = 0.0043 and *P = 0.0207 by one-way ANOVA with Dunnett´s multiple comparison test to non-ND.
Figure 7 Sarkospin extracts from AD patients with Tau/TDP-43 co-pathology (AD+) show a lower Tau seeding potency compared to AD patients with Tau-only pathology (AD−) and contain TDP-43 seeding competent species. (A) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using SarkoSpin patient extracts as seeds; created with BioRender.com. (B) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding the cells with non-ND 1, FTLD-Tau 2, AD − 2, AD + 2, FTLD-TDP 5, or PD 2 SarkoSpin extracts. Scale bar: 70 µm in overview and 15 µm in inset. (C) Quantification of number and area of aggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. ****P < 0.0001, **P = 0.0030, and *P = 0.0317 (number of aggregates), and ****P < 0.0001, **P = 0.0033, and *P = 0.0173 (area of aggregates) by one-way ANOVA with Šídák´s multiple comparison test to non-ND. (D) Scheme of TDP-43 seeding assay using doxycycline-inducible TDP-43-HA HEK293 cells; created with BioRender.com. (E) Representative confocal images of cytosolic pS409/410-positive TDP-43 neoaggregates in HEK293 cells, after transfection with non-ND 1, FTLD-TDP 5, AD + 2, AD − 2, FTLD-Tau 2, or PD 2 SarkoSpin patient extracts. DAPI is depicted in blue, HA staining in green, and pS409/410 in magenta. Scale bar: 50 µm in overview and 10 µm in inset. (F) Quantification of HA and pS409/410-TDP-43 colocalization as number and area of neoaggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. **P = 0.0043 and *P = 0.0207 by one-way ANOVA with Dunnett´s multiple comparison test to non-ND.CC BY · PubMed Central

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Research works printed but not linked: 101

  1. Afroz T, Hock E-M, Ernst P, Foglieni C, Jambeau M, Gilhespy LAB, Laferriere F, Maniecka Z, Plückthun A, Mittl P, Paganetti P, Allain FHT, Polymenidou M (2017) Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat Commun 8:45. https://doi.org/10.1038/s41467-017-00062-0 · DOI
  2. Alberti S, Dormann D (2019) Liquid-liquid phase separation in disease. Annu Rev Genet 53:171–194. https://doi.org/10.1146/annurev-genet-112618-043527 · DOI
  3. Alberti S, Gladfelter A, Mittag T (2019) Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176:419–434. https://doi.org/10.1016/j.cell.2018.12.035 · DOI · Paper page
  4. Alberti S, Hyman AA (2016) Are aberrant phase transitions a driver of cellular aging?. BioEssays N Rev Mol Cell Dev Biol 38:959–968. https://doi.org/10.1002/bies.201600042 · DOI
  5. Amador-Ortiz C, Lin W-L, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. https://doi.org/10.1002/ana.21154 · DOI · Paper page
  6. Ash PEA, Lei S, Shattuck J, Boudeau S, Carlomagno Y, Medalla M, Mashimo BL, Socorro G, Al-Mohanna LFA, Jiang L, Öztürk MM, Knobel M, Ivanov P, Petrucelli L, Wegmann S, Kanaan NM, Wolozin B (2021) TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau. Proc Natl Acad Sci USA 118:e2014188118. https://doi.org/10.1073/pnas.2014188118 · DOI · Paper page
  7. Barghorn S, Biernat J, Mandelkow E (2005) Purification of recombinant tau protein and preparation of Alzheimer-paired helical filaments in vitro. Methods Mol Biol 299:35–51. https://doi.org/10.1385/1-59259-874-9:035 · DOI
  8. Barghorn S, Zheng-Fischhöfer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E (2000) Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 39:11714–11721. https://doi.org/10.1021/bi000850r · DOI
  9. Bentmann E, Neumann M, Tahirovic S, Rodde R, Dormann D, Haass C (2012) Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43). J Biol Chem 287:23079–23094. https://doi.org/10.1074/jbc.M111.328757 · DOI
  10. Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer C, Rosenberry TL, Lewis J, Hutton M, Janus C (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27:3650–3662. https://doi.org/10.1523/JNEUROSCI.0587-07.2007 · DOI
  11. Boczek EE, Fürsch J, Niedermeier ML, Jawerth L, Jahnel M, Ruer-Gruß M, Kammer K-M, Heid P, Mediani L, Wang J, Yan X, Pozniakovski A, Poser I, Mateju D, Hubatsch L, Carra S, Alberti S, Hyman AA, Stengel F (2021) HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain. eLife 10:e69377. https://doi.org/10.7554/eLife.69377 · DOI
  12. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278. https://doi.org/10.1016/0197-4580(95)00021-6 discussion 278-284 · DOI · Paper page
  13. Chakraborty P, Ibáñez De Opakua A, Purslow JA, Fromm SA, Chatterjee D, Zachrdla M, Zhuang S, Puri S, Wolozin B, Zweckstetter M (2024) GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer’s disease-like filaments. Proc Natl Acad Sci 121:e2414176121. https://doi.org/10.1073/pnas.2414176121 · DOI · Paper page
  14. Chang C, Wu T-H, Wu C-Y, Chiang M, Toh EK-W, Hsu Y-C, Lin K-F, Liao Y, Huang T, Huang JJ-T (2012) The N-terminus of TDP-43 promotes its oligomerization and enhances DNA binding affinity. Biochem Biophys Res Commun 425:219–224. https://doi.org/10.1016/j.bbrc.2012.07.071 · DOI
  15. Chou C-C, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG, Chen YH, Duong DM, Seyfried NT, Powers MA, Kukar T, Hales CM, Gearing M, Cairns NJ, Boylan KB, Dickson DW, Rademakers R, Zhang Y-J, Petrucelli L, Sattler R, Zarnescu DC, Glass JD, Rossoll W (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci 21:228–239. https://doi.org/10.1038/s41593-017-0047-3 · DOI
  16. Clippinger AK, D’Alton S, Lin W-L, Gendron TF, Howard J, Borchelt DR, Cannon A, Carlomagno Y, Chakrabarty P, Cook C, Golde TE, Levites Y, Ranum L, Schultheis PJ, Xu G, Petrucelli L, Sahara N, Dickson DW, Giasson B, Lewis J (2013) Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy. Acta Neuropathol 126:39–50. https://doi.org/10.1007/s00401-013-1123-8 · DOI
  17. Combe CW, Graham M, Kolbowski L, Fischer L, Rappsilber J (2024) xiVIEW: visualisation of crosslinking mass spectrometry data. J Mol Biol 436:168656. https://doi.org/10.1016/j.jmb.2024.168656 · DOI
  18. Conicella AE, Dignon GL, Zerze GH, Schmidt HB, D’Ordine AM, Kim YC, Rohatgi R, Ayala YM, Mittal J, Fawzi NL (2020) TDP-43 α-helical structure tunes liquid-liquid phase separation and function. Proc Natl Acad Sci USA 117:5883–5894. https://doi.org/10.1073/pnas.1912055117 · DOI
  19. Conicella AE, Zerze GH, Mittal J, Fawzi NL (2016) ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Struct Lond Engl 24:1537–1549. https://doi.org/10.1016/j.str.2016.07.007 1993 · DOI
  20. Cox J, Mann M (2008) MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26:1367–1372. https://doi.org/10.1038/nbt.1511 · DOI · Paper page
  21. Czub MP, Uliana F, Grubić T, Padeste C, Rosowski KA, Lorenz C, Dufresne ER, Menzel A, Vakonakis I, Gasser U, Steinmetz MO (2025) Phase separation of a microtubule plus-end tracking protein into a fluid fractal network. Nat Commun 16:1165. https://doi.org/10.1038/s41467-025-56468-8 · DOI · Paper page
  22. D’Angelo MA, Raices M, Panowski SH, Hetzer MW (2009) Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell 136:284–295. https://doi.org/10.1016/j.cell.2008.11.037 · DOI · Paper page
  23. Das T, Zaidi FK, Farag M, Ruff KM, Mahendran TS, Singh A, Gui X, Messing J, Taylor JP, Banerjee PR, Pappu RV, Mittag T (2025) Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation. Mol Cell 85:2230–2245.e7. https://doi.org/10.1016/j.molcel.2025.05.011 · DOI
  24. Davis SA, Gan KA, Dowell JA, Cairns NJ, Gitcho MA (2017) TDP-43 expression influences amyloid β plaque deposition and tau aggregation. Neurobiol Dis 103:154–162. https://doi.org/10.1016/j.nbd.2017.04.012 · DOI
  25. De Rossi P, Lewis AJ, Furrer J, De Vos L, Demeter T, Zbinden A, Zhong W, Wiersma VI, Scialo C, Weber J, Guo Z, Scaramuzza S, Di Fabrizio M, Böing C, Castaño-Díez D, Al-Amoudi A, Pérez-Berlanga M, Lashley T, Stahlberg H, Polymenidou M (2021) FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade. EMBO Rep 22:e53877. https://doi.org/10.15252/embr.202153877 · DOI
  26. Deutsch EW, Bandeira N, Perez-Riverol Y, Sharma V, Carver JJ, Mendoza L, Kundu DJ, Wang S, Bandla C, Kamatchinathan S, Hewapathirana S, Pullman BS, Wertz J, Sun Z, Kawano S, Okuda S, Watanabe Y, MacLean B, MacCoss MJ, Zhu Y, Ishihama Y, Vizcaíno JA (2023) The ProteomeXchange consortium at 10 years: 2023 update. Nucleic Acids Res 51:D1539–D1548. https://doi.org/10.1093/nar/gkac1040 · DOI
  27. Dewey CM, Cenik B, Sephton CF, Dries DR, Mayer P, Good SK, Johnson BA, Herz J, Yu G (2011) TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol 31:1098–1108. https://doi.org/10.1128/MCB.01279-10 · DOI
  28. Dhakal S, Mondal M, Mirzazadeh A, Banerjee S, Ghosh A, Rangachari V (2023) α-Synuclein emulsifies TDP-43 prion-like domain—RNA liquid droplets to promote heterotypic amyloid fibrils. Commun Biol 6:1227. https://doi.org/10.1038/s42003-023-05608-1 · DOI
  29. Dujardin S, Hyman BT (2019) Tau prion-like propagation: state of the art and current challenges. Adv Exp Med Biol 1184:305–325. https://doi.org/10.1007/978-981-32-9358-8_23 · DOI · Paper page
  30. Eidenmüller J, Fath T, Maas T, Pool M, Sontag E, Brandt R (2001) Phosphorylation-mimicking glutamate clusters in the proline-rich region are sufficient to simulate the functional deficiencies of hyperphosphorylated tau protein. Biochem J 357:759–767. https://doi.org/10.1042/0264-6021:3570759 · DOI
  31. Emmanouilidis L, Bartalucci E, Kan Y, Ijavi M, Pérez ME, Afanasyev P, Boehringer D, Zehnder J, Parekh SH, Bonn M, Michaels TCT, Wiegand T, Allain FH-T (2024) A solid beta-sheet structure is formed at the surface of FUS droplets during aging. Nat Chem Biol. https://doi.org/10.1038/s41589-024-01573-w · DOI
  32. French RL, Grese ZR, Aligireddy H, Dhavale DD, Reeb AN, Kedia N, Kotzbauer PT, Bieschke J, Ayala YM (2019) Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation. J Biol Chem 294:6696–6709. https://doi.org/10.1074/jbc.RA118.005889 · DOI
  33. Gracia P, Polanco D, Tarancón-Díez J, Serra I, Bracci M, Oroz J, Laurents DV, García I, Cremades N (2022) Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau. Nat Commun 13:4586. https://doi.org/10.1038/s41467-022-32350-9 · DOI
  34. Gruijs da Silva LA, Simonetti F, Hutten S, Riemenschneider H, Sternburg EL, Pietrek LM, Gebel J, Dötsch V, Edbauer D, Hummer G, Stelzl LS, Dormann D (2022) Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. EMBO J 41:e108443. https://doi.org/10.15252/embj.2021108443 · DOI · Paper page
  35. Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133:665–704. https://doi.org/10.1007/s00401-017-1707-9 · DOI · Paper page
  36. Halfmann R, Lindquist S (2008) Screening for amyloid aggregation by semi-denaturing detergent-agarose gel electrophoresis. J Vis Exp. https://doi.org/10.3791/838 · DOI
  37. Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S, Hyman BT, Alberti S, Diez S, Hyman AA (2017) Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase. Cell Rep 20:2304–2312. https://doi.org/10.1016/j.celrep.2017.08.042 · DOI · Paper page
  38. Hofweber M, Hutten S, Bourgeois B, Spreitzer E, Niedner-Boblenz A, Schifferer M, Ruepp M-D, Simons M, Niessing D, Madl T, Dormann D (2018) Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173:706–719.e13. https://doi.org/10.1016/j.cell.2018.03.004 · DOI
  39. Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1411649111 · DOI · Paper page
  40. Hoyer W, Antony T, Cherny D, Heim G, Jovin TM, Subramaniam V (2002) Dependence of alpha-synuclein aggregate morphology on solution conditions. J Mol Biol 322:383–393. https://doi.org/10.1016/s0022-2836(02)00775-1 · DOI
  41. Hutten S, Usluer S, Bourgeois B, Simonetti F, Odeh HM, Fare CM, Czuppa M, Hruska-Plochan M, Hofweber M, Polymenidou M, Shorter J, Edbauer D, Madl T, Dormann D (2020) Nuclear import receptors directly bind to arginine-rich dipeptide repeat proteins and suppress their pathological interactions. Cell Rep 33:108538. https://doi.org/10.1016/j.celrep.2020.108538 · DOI
  42. Jaqaman K, Loerke D, Mettlen M, Kuwata H, Grinstein S, Schmid SL, Danuser G (2008) Robust single-particle tracking in live-cell time-lapse sequences. Nat Methods 5:695–702. https://doi.org/10.1038/nmeth.1237 · DOI
  43. Josephs KA, Dickson DW, Tosakulwong N, Weigand SD, Murray ME, Petrucelli L, Liesinger AM, Senjem ML, Spychalla AJ, Knopman DS, Parisi JE, Petersen RC, Jack CR, Whitwell JL (2017) Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer’s disease: a longitudinal retrospective study. Lancet Neurol 16:917–924. https://doi.org/10.1016/S1474-4422(17)30284-3 · DOI · Paper page
  44. Josephs KA, Murray ME, Whitwell JL, Parisi JE, Petrucelli L, Jack CR, Petersen RC, Dickson DW (2014a) Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 127:441–450. https://doi.org/10.1007/s00401-013-1211-9 · DOI · Paper page
  45. Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF, Ivnik RJ, Smith GE, Jack CR, Parisi JE, Petersen RC, Dickson DW (2014b) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127:811–824. https://doi.org/10.1007/s00401-014-1269-z · DOI · Paper page
  46. Kadokura A, Yamazaki T, Lemere CA, Takatama M, Okamoto K (2009) Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology. Neuropathol J Jpn Soc Neuropathol 29:566–573. https://doi.org/10.1111/j.1440-1789.2009.01017.x · DOI
  47. Kanaan NM, Hamel C, Grabinski T, Combs B (2020) Liquid-liquid phase separation induces pathogenic tau conformations in vitro. Nat Commun 11:2809. https://doi.org/10.1038/s41467-020-16580-3 · DOI · Paper page
  48. Koulouras G, Panagopoulos A, Rapsomaniki MA, Giakoumakis NN, Taraviras S, Lygerou Z (2018) EasyFRAP-web: a web-based tool for the analysis of fluorescence recovery after photobleaching data. Nucleic Acids Res 46:W467–W472. https://doi.org/10.1093/nar/gky508 · DOI
  49. Laferrière F, Maniecka Z, Pérez-Berlanga M, Hruska-Plochan M, Gilhespy L, Hock E-M, Wagner U, Afroz T, Boersema PJ, Barmettler G, Foti SC, Asi YT, Isaacs AM, Al-Amoudi A, Lewis A, Stahlberg H, Ravits J, De Giorgi F, Ichas F, Bezard E, Picotti P, Lashley T, Polymenidou M (2019) TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Nat Neurosci 22:65–77. https://doi.org/10.1038/s41593-018-0294-y · DOI
  50. Lashley T, Rohrer JD, Bandopadhyay R, Fry C, Ahmed Z, Isaacs AM, Brelstaff JH, Borroni B, Warren JD, Troakes C, King A, Al-Saraj S, Newcombe J, Quinn N, Ostergaard K, Schrøder HD, Bojsen-Møller M, Braendgaard H, Fox NC, Rossor MN, Lees AJ, Holton JL, Revesz T (2011) A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain J Neurol 134:2548–2564. https://doi.org/10.1093/brain/awr160 · DOI
  51. Latimer CS, Liachko NF (2021) Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease. GeroScience 43:1627–1634. https://doi.org/10.1007/s11357-021-00407-0 · DOI
  52. Latimer CS, Stair JG, Hincks JC, Currey HN, Bird TD, Keene CD, Kraemer BC, Liachko NF (2022) TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans. Dis Model Mech 15:dmm049323. https://doi.org/10.1242/dmm.049323 · DOI
  53. Leitner A, Walzthoeni T, Aebersold R (2014) Lysine-specific chemical cross-linking of protein complexes and identification of cross-linking sites using LC-MS/MS and the xQuest/xProphet software pipeline. Nat Protoc 9:120–137. https://doi.org/10.1038/nprot.2013.168 · DOI
  54. Ling S-C, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. https://doi.org/10.1016/j.neuron.2013.07.033 · DOI · Paper page
  55. Linsenmeier M, Faltova L, Morelli C, Capasso Palmiero U, Seiffert C, Küffner AM, Pinotsi D, Zhou J, Mezzenga R, Arosio P (2023) The interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils. Nat Chem 15:1340–1349. https://doi.org/10.1038/s41557-023-01289-9 · DOI
  56. Lipiński WP, Visser BS, Robu I, Fakhree MAA, Lindhoud S, Claessens MMAE, Spruijt E (2022) Biomolecular condensates can both accelerate and suppress aggregation of α-synuclein. Sci Adv 8:eabq6495. https://doi.org/10.1126/sciadv.abq6495 · DOI
  57. Meneses A, Koga S, O’Leary J, Dickson DW, Bu G, Zhao N (2021) TDP-43 pathology in Alzheimer’s disease. Mol Neurodegener 16:84. https://doi.org/10.1186/s13024-021-00503-x · DOI
  58. Mixed-Effects Models in S and S-PLUS (2000) Statistics and computing. Springer-Verlag, New York
  59. Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP (2015) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163:123–133. https://doi.org/10.1016/j.cell.2015.09.015 · DOI · Paper page
  60. Montalbano M, McAllen S, Cascio FL, Sengupta U, Garcia S, Bhatt N, Ellsworth A, Heidelman EA, Johnson OD, Doskocil S, Kayed R (2020) TDP-43 and tau oligomers in Alzheimer’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Neurobiol Dis 146:105130. https://doi.org/10.1016/j.nbd.2020.105130 · DOI
  61. Nedelsky NB, Taylor JP (2019) Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease. Nat Rev Neurol 15:272–286. https://doi.org/10.1038/s41582-019-0157-5 · DOI
  62. Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I, Attems J, Brayne C, Coyle-Gilchrist ITS, Chui HC, Fardo DW, Flanagan ME, Halliday G, Hokkanen SRK, Hunter S, Jicha GA, Katsumata Y, Kawas CH, Keene CD, Kovacs GG, Kukull WA, Levey AI, Makkinejad N, Montine TJ, Murayama S, Murray ME, Nag S, Rissman RA, Seeley WW, Sperling RA, White Iii CL, Yu L, Schneider JA (2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain J Neurol 142:1503–1527. https://doi.org/10.1093/brain/awz099 · DOI · Paper page
  63. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM-Y (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108 · DOI · Paper page
  64. Nuscher B, Kamp F, Mehnert T, Odoy S, Haass C, Kahle PJ, Beyer K (2004) Alpha-synuclein has a high affinity for packing defects in a bilayer membrane: a thermodynamics study. J Biol Chem 279:21966–21975. https://doi.org/10.1074/jbc.M401076200 · DOI
  65. Oakley SS, Maina MB, Marshall KE, Al-Hilaly YK, Harrington CR, Wischik CM, Serpell LC (2020) Tau filament self-assembly and structure: tau as a therapeutic target. Front Neurol 11:590754. https://doi.org/10.3389/fneur.2020.590754 · DOI
  66. Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J, Saha S, Franzmann TM, Pozniakovski A, Poser I, Maghelli N, Royer LA, Weigert M, Myers EW, Grill S, Drechsel D, Hyman AA, Alberti S (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066–1077. https://doi.org/10.1016/j.cell.2015.07.047 · DOI · Paper page
  67. Perez-Riverol Y, Bandla C, Kundu DJ, Kamatchinathan S, Bai J, Hewapathirana S, John NS, Prakash A, Walzer M, Wang S, Vizcaíno JA (2025) The PRIDE database at 20 years: 2025 update. Nucleic Acids Res 53:D543–D553. https://doi.org/10.1093/nar/gkae1011 · DOI
  68. Polymenidou M, Cleveland DW (2011) The seeds of neurodegeneration: prion-like spreading in ALS. Cell 147:498–508. https://doi.org/10.1016/j.cell.2011.10.011 · DOI
  69. Rai SK, Khanna R, Avni A, Mukhopadhyay S (2023) Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates. Proc Natl Acad Sci USA 120:e2216338120. https://doi.org/10.1073/pnas.2216338120 · DOI
  70. Ratti A, Buratti E (2016) Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem 138:95–111. https://doi.org/10.1111/jnc.13625 · DOI
  71. Ray S, Singh N, Kumar R, Patel K, Pandey S, Datta D, Mahato J, Panigrahi R, Navalkar A, Mehra S, Gadhe L, Chatterjee D, Sawner AS, Maiti S, Bhatia S, Gerez JA, Chowdhury A, Kumar A, Padinhateeri R, Riek R, Krishnamoorthy G, Maji SK (2020) α-Synuclein aggregation nucleates through liquid-liquid phase separation. Nat Chem 12:705–716. https://doi.org/10.1038/s41557-020-0465-9 · DOI · Paper page
  72. Ruf VC, Nübling GS, Willikens S, Shi S, Schmidt F, Levin J, Bötzel K, Kamp F, Giese A (2019) Different effects of α-synuclein mutants on lipid binding and aggregation detected by single molecule fluorescence spectroscopy and ThT fluorescence-based measurements. ACS Chem Neurosci 10:1649–1659. https://doi.org/10.1021/acschemneuro.8b00579 · DOI
  73. Ruf VC, Shi S, Schmidt F, Weckbecker D, Nübling GS, Ködel U, Mollenhauer B, Giese A (2020) Potential sources of interference with the highly sensitive detection and quantification of alpha-synuclein seeds by qRT-QuIC. FEBS Open Bio 10:883–893. https://doi.org/10.1002/2211-5463.12844 · DOI
  74. Rummens J, Khalil B, Yıldırım G, Silva P, Zorzini V, Peredo N, Wojno M, Ramakers M, Van Den Bosch L, Van Damme P, Davie K, Hendrix J, Rousseau F, Schymkowitz J, Da Cruz S (2025) TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43. Neuron 113:1597–1613.e8. https://doi.org/10.1016/j.neuron.2025.03.004 · DOI
  75. Sahin C, Leppert A, Landreh M (2023) Advances in mass spectrometry to unravel the structure and function of protein condensates. Nat Protoc 18:3653–3661. https://doi.org/10.1038/s41596-023-00900-0 · DOI
  76. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J-Y, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019 · DOI · Paper page
  77. Scialò C, Zhong W, Jagannath S, Wilkins O, Caredio D, Hruska-Plochan M, Lurati F, Peter M, De Cecco E, Celauro L, Aguzzi A, Legname G, Fratta P, Polymenidou M (2025) Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures. Neuron 113:1614–1628.e11. https://doi.org/10.1016/j.neuron.2025.03.008 · DOI
  78. Shen YI, Chen A, Wang W, Shen Y, Ruggeri FS, Aime S, Wang Z, Qamar S, Espinosa JR, Garaizar A, St George-Hyslop P, Collepardo-Guevara R, Weitz DA, Vigolo D, Knowles TPJ (2023) The liquid-to-solid transition of FUS is promoted by the condensate surface. Proc Natl Acad Sci USA 120:e2301366120. https://doi.org/10.1073/pnas.2301366120 · DOI
  79. Shih Y-H, Tu L-H, Chang T-Y, Ganesan K, Chang W-W, Chang P-S, Fang Y-S, Lin Y-T, Jin L-W, Chen Y-R (2020) TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease. Nat Commun 11:5950. https://doi.org/10.1038/s41467-020-19786-7 · DOI
  80. Smith VD, Bachstetter AD, Ighodaro E, Roberts K, Abner EL, Fardo DW, Nelson PT (2017) Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi. Brain Pathol 28:264–273. https://doi.org/10.1111/bpa.12505 · DOI
  81. Spires-Jones TL, Attems J, Thal DR (2017) Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathology 134:187–205. https://doi.org/10.1007/s00401-017-1709-7 · DOI
  82. Stringer C, Pachitariu M (2025) Cellpose3: one-click image restoration for improved cellular segmentation. Nat Methods 22:592–599. https://doi.org/10.1038/s41592-025-02595-5 · DOI
  83. Takeda S, Wegmann S, Cho H, DeVos SL, Commins C, Roe AD, Nicholls SB, Carlson GA, Pitstick R, Nobuhara CK, Costantino I, Frosch MP, Müller DJ, Irimia D, Hyman BT (2015) Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat Commun 6:8490. https://doi.org/10.1038/ncomms9490 · DOI · Paper page
  84. Thomas DX, Bajaj S, McRae-McKee K, Hadjichrysanthou C, Anderson RM, Collinge J (2020) Association of TDP-43 proteinopathy, cerebral amyloid angiopathy, and Lewy bodies with cognitive impairment in individuals with or without Alzheimer’s disease neuropathology. Sci Rep 10:14579. https://doi.org/10.1038/s41598-020-71305-2 · DOI
  85. Tinevez J-Y, Perry N, Schindelin J, Hoopes GM, Reynolds GD, Laplantine E, Bednarek SY, Shorte SL, Eliceiri KW (2017) TrackMate: an open and extensible platform for single-particle tracking. Methods 115:80–90. https://doi.org/10.1016/j.ymeth.2016.09.016 · DOI
  86. Tomé SO, Gomes LA, Li X, Vandenberghe R, Tousseyn T, Thal DR (2021) TDP-43 interacts with pathological τ protein in Alzheimer’s disease. Acta Neuropathol. https://doi.org/10.1007/s00401-021-02295-2 · DOI
  87. Tomé SO, Tsaka G, Ronisz A, Ospitalieri S, Gawor K, Gomes LA, Otto M, Von Arnim CAF, Van Damme P, Van Den Bosch L, Ghebremedhin E, Laureyssen C, Sleegers K, Vandenberghe R, Rousseau F, Schymkowitz J, Thal DR (2023) TDP-43 pathology is associated with increased tau burdens and seeding. Mol Neurodegener 18:71. https://doi.org/10.1186/s13024-023-00653-0 · DOI
  88. Tomé SO, Vandenberghe R, Ospitalieri S, Van Schoor E, Tousseyn T, Otto M, von Arnim CAF, Thal DR (2020) Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes. Acta Neuropathol Commun 8:61. https://doi.org/10.1186/s40478-020-00934-5 · DOI
  89. Tremblay C, St-Amour I, Schneider J, Bennett DA, Calon F (2011) Accumulation of TAR DNA binding protein-43 (TDP-43) in mild cognitive impairment and Alzheimer disease. J Neuropathol Exp Neurol 70:788–798. https://doi.org/10.1097/NEN.0b013e31822c62cf · DOI
  90. Tziortzouda P, Van Den Bosch L, Hirth F (2021) Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation. Nat Rev Neurosci 22:197–208. https://doi.org/10.1038/s41583-021-00431-1 · DOI
  91. Uemura N, Uemura MT, Luk KC, Lee VM-Y, Trojanowski JQ (2020) Cell-to-cell transmission of tau and α-synuclein. Trends Mol Med 26:936–952. https://doi.org/10.1016/j.molmed.2020.03.012 · DOI · Paper page
  92. Ukmar-Godec T, Hutten S, Grieshop MP, Rezaei-Ghaleh N, Cima-Omori MS, Biernat J, Mandelkow E, Söding J, Dormann D, Zweckstetter M (2019) Lysine/RNA-interactions drive and regulate biomolecular condensation. Nat Commun 10:2909. https://doi.org/10.1038/s41467-019-10792-y · DOI · Paper page
  93. Vanderweyde T, Yu H, Varnum M, Liu-Yesucevitz L, Citro A, Ikezu T, Duff K, Wolozin B (2012) Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J 32:8270–8283. https://doi.org/10.1523/JNEUROSCI.1592-12.2012 · DOI
  94. Wang A, Conicella AE, Schmidt HB, Martin EW, Rhoads SN, Reeb AN, Nourse A, Ramirez Montero D, Ryan VH, Rohatgi R, Shewmaker F, Naik MT, Mittag T, Ayala YM, Fawzi NL (2018) A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. EMBO J 37:e97452. https://doi.org/10.15252/embj.201797452 · DOI
  95. Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Laskowski PR, MacKenzie D, Kamath T, Commins C, Vanderburg C, Roe AD, Fan Z, Molliex AM, Hernandez-Vega A, Muller D, Hyman AA, Mandelkow E, Taylor JP, Hyman BT (2018) Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J 37:e98049. https://doi.org/10.15252/embj.201798049 · DOI · Paper page
  96. Wille H, Drewes G, Biernat J, Mandelkow EM, Mandelkow E (1992) Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J Cell Biol 118:573–584. https://doi.org/10.1083/jcb.118.3.573 · DOI · Paper page
  97. Wolozin B, Ivanov P (2019) Stress granules and neurodegeneration. Nat Rev Neurosci 20:649–666. https://doi.org/10.1038/s41583-019-0222-5 · DOI · Paper page
  98. Yan X, Kuster D, Mohanty P, Nijssen J, Pombo-García K, Garcia Morato J, Rizuan A, Franzmann TM, Sergeeva A, Ly AM, Liu F, Passos PM, George L, Wang S-H, Shenoy J, Danielson HL, Ozguney B, Honigmann A, Ayala YM, Fawzi NL, Dickson DW, Rossoll W, Mittal J, Alberti S, Hyman AA (2025) Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates. Cell. https://doi.org/10.1016/j.cell.2025.04.039 · DOI
  99. Yılmaz Ş, Busch F, Nagaraj N, Cox J (2022) Accurate and automated high-coverage identification of chemically cross-linked peptides with MaxLynx. Anal Chem 94:1608–1617. https://doi.org/10.1021/acs.analchem.1c03688 · DOI
  100. Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN, Hernandez I, Guzman E, Kosik KS, Han S (2017) RNA stores tau reversibly in complex coacervates. PLoS Biol 15:e2002183. https://doi.org/10.1371/journal.pbio.2002183 · DOI · Paper page
  101. Zhang X, Vigers M, McCarty J, Rauch JN, Fredrickson GH, Wilson MZ, Shea J-E, Han S, Kosik KS (2020) The proline-rich domain promotes Tau liquid-liquid phase separation in cells. J Cell Biol 219:e202006054. https://doi.org/10.1083/jcb.202006054 · DOI · Paper page

Cited by

See all 23

Metadata

Authors
Simonetti, F., Zhong, W., Hutten, S., Uliana, F., Schifferer, M., Rezaei, A., Ramirez, L. M., Hochmair, J., Sankar, R., Gopalan, A., Kielisch, F., Riemenschneider, H., Ruf, V., Schmidt, C., Simons, M., Zweckstetter, M., Wegmann, S., Lashley, T., Polymenidou, M., Edbauer, D., & Dormann, D.
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2025-10-17
Volume
44
Issue
24
ISSN
  • 0261-4189
  • 1460-2075
DOI
10.1038/s44318-025-00590-2
PMC
PMC12706024
Cited by
23
References
19
Language
en
Licence
Funders
  • Alzheimers Research Award by the Hans and Isle Breuer Foundation
  • Deutsche Forschungsgemeinschaft (442698351, 390857198, 408885537, 497669232, INST 247/912-1FUGG)
  • Swiss National Science Foundation (310030_192650)
  • Marie Curie Individual Fellowship (101207537)
  • SPP2191 (419138680, 419139133)
  • SFB1551 (464588647)
  • Ministry of Science and Health of Rhineland-Palatinate and the European Regional Development Fund (84012490)
  • Association for Frontotemporal Dementia
  • Bundesministerium für Bildung und Forschung (03Z22HN22)

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Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.