Article Dans Une Revue iScience Année : 2025

Application of modular isoxazoline-β$^{2,2-}$amino acid-based peptidomimetics as chemical model systems for studying the tau misfolding

Résumé

Tau is a microtubule-associated protein essential for regulating microtubule dynamics and axonal transport in neurons. In tauopathies, the transition of tau from a physiological to a pathological form remains unclear, though the hexapeptides PHF6 and PHF6∗ are key in triggering aggregation. These sequences are shielded by a β-hairpin structure in the native state but expose hydrophobic residues during misfolding, promoting self-assembly. This study employs a non-natural β2-amino acid to induce PHF6 and PHF6∗ into either extended or β-hairpin conformations. The extended form triggers tau aggregation without additives, acting as a seed-competent monomer model system. Conversely, the β-hairpin preserves tau in a soluble monomeric state. Additionally, a β-hairpin mimic inspired by Hsp90 showed potential as a chaperone mimic and inhibitor of tau aggregation, offering insights into corrective folding and aggregation modulation in neuronal environments.

Domaines

Fichier principal
Vignette du fichier
DiLorenzo iScience 2025.pdf (5.45 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)
Licence

Dates et versions

hal-05056022 , version 1 (05-05-2025)

Licence

Identifiants

Citer

Davide Di Lorenzo, Nicolo Bisi, Raffaella Bucci, Inga Ennen, Leonardo Lo Presti, et al.. Application of modular isoxazoline-β$^{2,2-}$amino acid-based peptidomimetics as chemical model systems for studying the tau misfolding. iScience, 2025, 28 (4), pp.112272. ⟨10.1016/j.isci.2025.112272⟩. ⟨hal-05056022⟩
49 Consultations
99 Téléchargements

Altmetric

Partager

  • More