TY  - JOUR
AU  - Simonetti, Francesca
AU  - Zhong, Weijia
AU  - Hutten, Saskia
AU  - Uliana, Federico
AU  - Schifferer, Martina
AU  - Rezaei, Ali
AU  - Ramirez, Lisa Marie
AU  - Hochmair, Janine
AU  - Sankar, Rithika
AU  - Gopalan, Anusha
AU  - Kielisch, Fridolin
AU  - Riemenschneider, Henrick
AU  - Ruf, Viktoria
AU  - Schmidt, Carla
AU  - Simons, Mikael
AU  - Zweckstetter, Markus
AU  - Wegmann, Susanne
AU  - Lashley, Tammaryn
AU  - Polymenidou, Magdalini
AU  - Edbauer, Dieter
AU  - Dormann, Dorothee
TI  - Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding.
JO  - The EMBO journal
VL  - 44
IS  - 24
SN  - 0261-4189
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2025-01370
SP  - 7395 - 7433
PY  - 2025
AB  - 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.
KW  - tau Proteins: metabolism
KW  - tau Proteins: genetics
KW  - Humans
KW  - DNA-Binding Proteins: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: genetics
KW  - Protein Aggregation, Pathological: metabolism
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Protein Aggregates
KW  - Protein Binding
KW  - Alzheimer’s Disease (Other)
KW  - Phase Separation (Other)
KW  - Seeding (Other)
KW  - TDP-43 (Other)
KW  - Tau (Other)
KW  - tau Proteins (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - TARDBP protein, human (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41107545
DO  - DOI:10.1038/s44318-025-00590-2
UR  - https://pub.dzne.de/record/282909
ER  -