Abstract
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.
Highlights
Pathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases
By measuring the concentration of the monomeric protein left after reaching Thioflavin T (ThT) saturation, we found that ~80% of 2N4R tau was aggregated (Supplementary Fig. 1)
We currently do not know why the structure of tau fibrils is different in different diseases and which molecular factors drive tau into disease-specific amyloid fibril structures
Summary
Pathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. Pathological aggregation of the microtubule-binding protein tau (Fig. 1a) into amyloid fibrils is a hallmark of different neurodegenerative diseases collectively termed tauopathies[1]. Cryo-electron microscopy (cryoEM) of heparin-induced fibrils of the longest isoform of tau (2N4R tau; Fig. 1a) demonstrated that the heparin-induced fibrils differ structurally from the tau filaments extracted from human patient brain (Fig. 1b, c)[10] Another major drawback of the heparin-based in vitro fibrilization assay is the high negative charge of heparin: heparin-induced tau fibrillization has been extensively used to search for small molecules as tau aggregation inhibitors[11,12], potentially generating false hits due to electrostatic interactions between the small molecules and heparin. Using a combination of biochemical experiments and NMR spectroscopy we provide evidence that the co-factor-free tau fibrils have structural properties that largely differ from those of heparin-induced tau fibrils. We show that the tau fibrils aggregated in the absence of heparin display certain properties of amyloid fibrils from patient material, including a similar size and location of the fibrillar core,
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