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

Chakraborty, P., Rivière, G., Liu, S., Ibáñez de Opakua, A., Dervişoğlu, R., Hebestreit, A., et al. (2021). Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils. Nature Communications, 12: 4231. doi:10.1038/s41467-021-24362-8.

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Chakraborty, P., Author
Rivière, G., Author
Liu, S., Author
Ibáñez de Opakua, A., Author
Dervişoğlu, R.1, Author              
Hebestreit, A., Author
Andreas, L. B.1, Author              
Vorberg, I. M., Author
Zweckstetter, M.2, Author              
Affiliations:
1Research Group of Solid State NMR Spectroscopy-2, MPI for Biophysical Chemistry, Max Planck Society, ou_2396693              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: Alzheimer's disease; Solid-state NMR; Structural biology
 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.

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Language(s): eng - English
 Dates: 2021-07-09
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-021-24362-8
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Title: Nature Communications
Source Genre: Journal
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Pages: 12 Volume / Issue: 12 Sequence Number: 4231 Start / End Page: - Identifier: -