Title :

Precision proteoform design for 4R tau isoform selective templated aggregation

Author(s) :

Longhini, A. P. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Dubose, A. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Lobo, S. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Vijayan, V. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Bai, Y. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Rivera, E. K. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Sala-Jarque, J. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Nikitina, A. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Carrettiero, D. C. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Unger, M. T. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Sclafani, O. R. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Fu, V. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Beckett, E. R. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Vigers, M. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Buee, Luc [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Landrieu, Isabelle [Auteur]
Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167
Shell, S. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Shea, J. E. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Han, S. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Kosik, K. S. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]

Journal title :

Proceedings of the National Academy of Sciences of the United States of America

Abbreviated title :

Proc Natl Acad Sci U S A

Volume number :

121

Pages :

e2320456121

Publication date :

2024-04-10

ISSN :

1091-6490

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau folds and stacks into seeding-competent ...
Show more >Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high β-sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting β-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19-residue peptide. These peptide fibrils function as partial prions to recruit naive 4R tau—ten times the length of the peptide—and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform–specific therapeutic interventions.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167
• Lille Neurosciences & Cognition (LilNCog) - U 1172

Submission date :

2024-05-06T22:35:29Z
2024-09-03T08:23:54Z
2024-09-03T08:37:18Z