Intrinsic aggregation and propagation of unmodified tau peptides: R2R3 as a minimal model system
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
40515399
DOI
10.1016/j.bpj.2025.06.009
PII: S0006-3495(25)00369-8
Knihovny.cz E-resources
- MeSH
- Kinetics MeSH
- Humans MeSH
- Protein Aggregates * MeSH
- tau Proteins * chemistry metabolism MeSH
- Amino Acid Sequence MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Protein Aggregates * MeSH
- tau Proteins * MeSH
Tau aggregation into neurofibrillary tangles is a defining feature of Alzheimer's disease and other tauopathies. Although aggregation depends largely on specific amyloidogenic motifs (particularly VQIINK and VQIVYK) in repeated regions of tau microtubule-binding domains, how the primary sequence of adjacent repeats intrinsically influences aggregation and prion-like propagation remains unclear. This study systematically characterized three unmodified, physiologically relevant tau peptide constructs-R1R3, R2R3, and R3R4-to define their intrinsic aggregation kinetics, structural features, and prion-like seeding activity. Among these constructs, we found that R2R3 showed rapid aggregation, distinct β-sheet formation, and potent seeding capable of sustained secondary propagation in cellular biosensor assays. Whereas recent studies have highlighted chemically modified peptides (e.g., acetylated and phosphomimic peptides), our study emphasizes the importance of native, unmodified sequences as fundamental determinants in tau aggregation. Furthermore, these findings establish R2R3 as a robust minimal tau model, providing a valuable tool for mechanistic research and therapeutic screening in tau-related neurodegeneration.
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