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University of California, Santa Barbara

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Proc. Natl. Acad. Sci. USA, Apr 09 2024, 121 (15) | https://doi.org/10.1073/pnas.2320456121 Precision proteoform design for 4R tau isoform selective templated aggregation

Andrew P Longhini^{1 2}, Austin DuBose ³, Samuel Lobo ⁴, Vishnu Vijayan ³, Yeran Bai ^{1 2 5}, Erica Keane Rivera ^{1 2}, Julia Sala-Jarque^{1 2}, Arina Nikitina ^{1 2}, Daniel C Carrettiero^{1 2 6}, Matthew T Unger ^{1 2}, Olivia R Sclafani ^{1 2}, Valerie Fu ^{1 2}, Emily R Beckett ^{1 2}, Michael Vigers ³, Luc Buée ^{7 8}, Isabelle Landrieu ^{9 10}, Scott Shell ⁴, Joan E Shea ^{3 11}, Songi Han ^{3 4 *}, Kenneth S Kosik ^{1 2 *}

¹Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106.

²Department of Molecular, Cell and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106.

³Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106.

⁴Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA 93106.

⁵Photothermal Spectroscopy Corp., Santa Barbara, CA 93101.

⁶Center for Natural and Human Sciences, Federal University of ABC, São Bernardo do Campo, São Paulo 09600-000, Brazil.

⁷University of Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition Lille F-59000, France.

⁸Laboratoire d'Excellence Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease, Alzheimer & Tauopathies Team, Lille F-59000, France.

⁹Center National de la Recherche Scientifique Équipe de Recherche 9002-Integrative Structural Biology, Lille F-59000, France.

¹⁰University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1167-Risk Factors and Molecular Determinants of Aging-Related Diseases Lille F-59000, France.

¹¹Department of Physics, University of California Santa Barbara, Santa Barbara, CA 93106.

^*Corresponding authors: correspondence to Songi Han or Kenneth S Kosik

Abstract

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.

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형식Research article
게재일2024년 04월 (BRIC 등록일 2024-05-10)
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