Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding
Francesca Simonetti, Weijia Zhong, Saskia Hutten, Federico Uliana, Martina Schifferer, Ali Rezaei, Lisa Marie Ramirez, Janine Hochmair, Rithika Sankar, Anusha B. Gopalan, Fridolin Kielisch, Henrick Riemenschneider, Viktoria Ruf, Carla Schmidt, Mikael Simons, Markus Zweckstetter, Susanne Wegmann, Tammaryn Lashley, Magdalini Polymenidou, Dieter Edbauer, Dorothee Dormann
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.