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

Pijush Chakraborty, Gwladys Rivière, Shu Liu, Alain Ibáñez Opakua, Rıza Dervişoğlu, Alina Hebestreit, Loren B. Andreas, Ina M. Vorberg and Markus Zweckstetter ()
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Pijush Chakraborty: German Center for Neurodegenerative Diseases (DZNE)
Gwladys Rivière: German Center for Neurodegenerative Diseases (DZNE)
Shu Liu: German Center for Neurodegenerative Diseases (DZNE)
Alain Ibáñez Opakua: German Center for Neurodegenerative Diseases (DZNE)
Rıza Dervişoğlu: Max Planck Institute for Biophysical Chemistry
Alina Hebestreit: German Center for Neurodegenerative Diseases (DZNE)
Loren B. Andreas: Max Planck Institute for Biophysical Chemistry
Ina M. Vorberg: German Center for Neurodegenerative Diseases (DZNE)
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24362-8

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