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<p>Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion-like spread of aggregates. Within these filaments, tau protomers always exhibit a cross-β amyloid structure. However, distinct cross-β amyloid folds correlate with specific diseases. An understanding of how these conformations impact seeding activity remains elusive. Identifying the minimal epitopes required for transcellular propagation of tau aggregates represents a key step towards more relevant models of disease progression. Here we implement a diversity-oriented peptide macrocyclization approach towards miniature tau, or ‘mini-tau’, proteomimetics that can seed the aggregation of tau in engineered cells and primary neurons. Structural elucidation of one such seed-competent macrocycle reveals remarkable conformational congruence with core folds from patient-derived extracts of tau. The ability to impart β-arch form and function through peptide stapling has broad-ranging implications for the minimization and mimicry of pathological tau and other amyloid proteins that drive neurodegeneration.</p><p></p>

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Macrocyclic β-arch peptides that mimic the structure and function of disease-associated tau folds

  • 期刊论文

  • 发表日期：

    2025年4月30日

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  • Isaac J. Angera,
  • Xueyong Xu,
  • Benjamin H. Rajewski,
  • Grace I. Hallinan,
  • Xiaoqi Zhang,
  • Bernardino Ghetti,
  • Ruben Vidal,
  • Wen Jiang,
  • Juan R. Del Valle

摘要

Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion-like spread of aggregates. Within these filaments, tau protomers always exhibit a cross-β amyloid structure. However, distinct cross-β amyloid folds correlate with specific diseases. An understanding of how these conformations impact seeding activity remains elusive. Identifying the minimal epitopes required for transcellular propagation of tau aggregates represents a key step towards more relevant models of disease progression. Here we implement a diversity-oriented peptide macrocyclization approach towards miniature tau, or ‘mini-tau’, proteomimetics that can seed the aggregation of tau in engineered cells and primary neurons. Structural elucidation of one such seed-competent macrocycle reveals remarkable conformational congruence with core folds from patient-derived extracts of tau. The ability to impart β-arch form and function through peptide stapling has broad-ranging implications for the minimization and mimicry of pathological tau and other amyloid proteins that drive neurodegeneration.