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@ARTICLE{Simonetti:282909,
      author       = {Simonetti, Francesca and Zhong, Weijia and Hutten, Saskia
                      and Uliana, Federico and Schifferer, Martina and Rezaei, Ali
                      and Ramirez, Lisa Marie and Hochmair, Janine and Sankar,
                      Rithika and Gopalan, Anusha and Kielisch, Fridolin and
                      Riemenschneider, Henrick and Ruf, Viktoria and Schmidt,
                      Carla and Simons, Mikael and Zweckstetter, Markus and
                      Wegmann, Susanne and Lashley, Tammaryn and Polymenidou,
                      Magdalini and Edbauer, Dieter and Dormann, Dorothee},
      title        = {{D}irect interaction between {TDP}-43 and {T}au promotes
                      their co-condensation, while suppressing {T}au fibril
                      formation and seeding.},
      journal      = {The EMBO journal},
      volume       = {44},
      number       = {24},
      issn         = {0261-4189},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2025-01370},
      pages        = {7395 - 7433},
      year         = {2025},
      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.},
      keywords     = {tau Proteins: metabolism / tau Proteins: genetics / Humans
                      / DNA-Binding Proteins: metabolism / DNA-Binding Proteins:
                      genetics / Alzheimer Disease: metabolism / Alzheimer
                      Disease: pathology / Alzheimer Disease: genetics / Protein
                      Aggregation, Pathological: metabolism / Brain: metabolism /
                      Brain: pathology / Protein Aggregates / Protein Binding /
                      Alzheimer’s Disease (Other) / Phase Separation (Other) /
                      Seeding (Other) / TDP-43 (Other) / Tau (Other) / tau
                      Proteins (NLM Chemicals) / DNA-Binding Proteins (NLM
                      Chemicals) / TARDBP protein, human (NLM Chemicals) / MAPT
                      protein, human (NLM Chemicals) / Protein Aggregates (NLM
                      Chemicals)},
      cin          = {AG Edbauer / AG Misgeld / AG Zweckstetter / AG Wegmann /
                      Clinical Research (Munich)},
      ddc          = {570},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)1110000-4 /
                      I:(DE-2719)1410001 / I:(DE-2719)1810006 /
                      I:(DE-2719)1111015},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351) / 353 - Clinical and Health Care Research
                      (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351 /
                      G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41107545},
      doi          = {10.1038/s44318-025-00590-2},
      url          = {https://pub.dzne.de/record/282909},
}