Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils.

Chakraborty, Pijush; Rivière, Gwladys; Liu, Shu; de Opakua, Alain Ibáñez; Dervişoğlu, Rıza; Hebestreit, Alina; Andreas, Loren B.; Vorberg, Ina M.; Zweckstetter, Markus

Pathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. The emergence of disease-specific tau aggregate structures termed tau strains, however, remains elusive. Here we show that full-length tau protein can be aggregated in the absence of co-factors into seeding-competent amyloid fibrils that sequester RNA. Using a combination of solid-state NMR spectroscopy and biochemical experiments we demonstrate that the co-factor-free amyloid fibrils of tau have a rigid core that is similar in size and location to the rigid core of tau fibrils purified from the brain of patients with corticobasal degeneration. In addition, we demonstrate that the N-terminal 30 residues of tau are immobilized during fibril formation, in agreement with the presence of an N-terminal epitope that is specifically detected by antibodies in pathological tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that the co-factor-free tau fibrils strongly sequester RNA. Taken together the study provides a critical advance to reveal the molecular factors that guide aggregation towards disease-specific tau strains. The authors present a method for the conversion of full-length tau protein into seeding-competent amyloid fibrils without heparin or other negatively charged co-factors, which could be useful for studying the effects of post-translational modifications on Tau aggregation as well as to identify potential inhibitors of tau aggregation. Biochemical experiments and solid-state NMR spectroscopy measurements show that these co-factor-free tau fibrils have similar properties as amyloid fibrils isolated from brain tissue but differ from those of commonly used heparin-induced tau fibrils.

TAU proteins; AMYLOID; N-terminal residues; POST-translational modification; NUCLEAR magnetic resonance spectroscopy; NEURODEGENERATION

Nature Communications, 2021, Vol 12, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-021-24362-8