Journal Articles ACS Chemical Neuroscience Year : 2024

Disruption of PHF6 Peptide Aggregation from Tau Protein: Mechanisms of Palmatine Chloride in Preventing Early PHF6 Aggregation

Perturbation de l'agrégation du PHF6 de la protéine Tau : Mécanismes d'action du chlorure de palmatine dans la prévention de l'agrégation précoce du PHF6

Abstract

The formation of neurofibrillary tangles (NFTs), composed of tau protein aggregates, is a hallmark of neuro- degenerative diseases known as tauopathies, including Alzheimer’s disease (AD). NFTs consist of paired helical filaments (PHFs) of tau protein with a dominant β-sheet secondary structure. Within these PHFs, the PHF6 hexapeptide (Val306-Gln-Ile-Val-Tyr-Lys311) has been commonly highlighted as a key site for tau protein nucleation. Palmatine chloride (PC) has been identified as an inhibitor of PHF6 aggregation, capable of reducing aggregation propensity at submicromolar concentrations. In pursuit of novel anti-AD drugs targeting early tau aggregation stages, we conducted an in silico study to elucidate PC’s mechanism of action during PHF6 aggregation. Our observations suggest that while PHF6 can still initiate self-aggregation in the presence of PC, PC molecules subtly influence PHF6 aggregation dynamics, favoring smaller aggregates over larger complexes. The study underlined the key roles of aromatic rings in PC binding to different PHF6 aggregates by interacting through π−π stacking with the PHF6 Tyr310 side chain. The presence of aromatic rings in compounds to be able to inhibit the earlier complexation phase seems to be essential. These in silico findings lay a foundation for the design of compounds that could intervene in resolving the neurotoxicity of protein aggregates in AD.
No file

Dates and versions

hal-04847910 , version 1 (19-12-2024)

Identifiers

Cite

Charline Fagnen, Johanna Giovannini, Thomas Vignol, Marc Since, Marco Catto, et al.. Disruption of PHF6 Peptide Aggregation from Tau Protein: Mechanisms of Palmatine Chloride in Preventing Early PHF6 Aggregation. ACS Chemical Neuroscience, 2024, 15 (21), pp.3981-3990. ⟨10.1021/acschemneuro.4c00353⟩. ⟨hal-04847910⟩
12 View
0 Download

Altmetric

Share

More