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Local structural preferences in shaping tau amyloid polymorphism

Nikolaos Louros, Martin Wilkinson, Grigoria Tsaka, Meine Ramakers, Chiara Morelli, Teresa Garcia, Rodrigo Gallardo, Sam D'Haeyer (UGent) , Vera Goossens (UGent) , Dominique Audenaert (UGent) , et al.
(2024) NATURE COMMUNICATIONS. 15(1).
Author
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Abstract
Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.
Keywords
General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary, PAIRED HELICAL FILAMENTS, CRYO-EM STRUCTURES, PROTEIN-TAU, PHOSPHORYLATION, AGGREGATION, DIVERSITY, TAUOPATHY, ISOFORMS

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MLA
Louros, Nikolaos, et al. “Local Structural Preferences in Shaping Tau Amyloid Polymorphism.” NATURE COMMUNICATIONS, vol. 15, no. 1, 2024, doi:10.1038/s41467-024-45429-2.
APA
Louros, N., Wilkinson, M., Tsaka, G., Ramakers, M., Morelli, C., Garcia, T., … Schymkowitz, J. (2024). Local structural preferences in shaping tau amyloid polymorphism. NATURE COMMUNICATIONS, 15(1). https://doi.org/10.1038/s41467-024-45429-2
Chicago author-date
Louros, Nikolaos, Martin Wilkinson, Grigoria Tsaka, Meine Ramakers, Chiara Morelli, Teresa Garcia, Rodrigo Gallardo, et al. 2024. “Local Structural Preferences in Shaping Tau Amyloid Polymorphism.” NATURE COMMUNICATIONS 15 (1). https://doi.org/10.1038/s41467-024-45429-2.
Chicago author-date (all authors)
Louros, Nikolaos, Martin Wilkinson, Grigoria Tsaka, Meine Ramakers, Chiara Morelli, Teresa Garcia, Rodrigo Gallardo, Sam D’Haeyer, Vera Goossens, Dominique Audenaert, Dietmar Rudolf Thal, Ian R. Mackenzie, Rosa Rademakers, Neil A. Ranson, Sheena E. Radford, Frederic Rousseau, and Joost Schymkowitz. 2024. “Local Structural Preferences in Shaping Tau Amyloid Polymorphism.” NATURE COMMUNICATIONS 15 (1). doi:10.1038/s41467-024-45429-2.
Vancouver
1.
Louros N, Wilkinson M, Tsaka G, Ramakers M, Morelli C, Garcia T, et al. Local structural preferences in shaping tau amyloid polymorphism. NATURE COMMUNICATIONS. 2024;15(1).
IEEE
[1]
N. Louros et al., “Local structural preferences in shaping tau amyloid polymorphism,” NATURE COMMUNICATIONS, vol. 15, no. 1, 2024.
@article{01HPGNX60ZX49NRP4DG05ZKCKZ,
  abstract     = {{Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.}},
  articleno    = {{1028}},
  author       = {{Louros, Nikolaos and Wilkinson, Martin and Tsaka, Grigoria and Ramakers, Meine and Morelli, Chiara and Garcia, Teresa and Gallardo, Rodrigo and D'Haeyer, Sam and Goossens, Vera and Audenaert, Dominique and Thal, Dietmar Rudolf and Mackenzie, Ian R. and Rademakers, Rosa and Ranson, Neil A. and Radford, Sheena E. and Rousseau, Frederic and Schymkowitz, Joost}},
  issn         = {{2041-1723}},
  journal      = {{NATURE COMMUNICATIONS}},
  keywords     = {{General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary,PAIRED HELICAL FILAMENTS,CRYO-EM STRUCTURES,PROTEIN-TAU,PHOSPHORYLATION,AGGREGATION,DIVERSITY,TAUOPATHY,ISOFORMS}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{16}},
  title        = {{Local structural preferences in shaping tau amyloid polymorphism}},
  url          = {{http://doi.org/10.1038/s41467-024-45429-2}},
  volume       = {{15}},
  year         = {{2024}},
}
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