Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids

• Published in: Scientific reports Vol. 8; no. 1; p. 71
• Main Authors: KrishnaKumar, V. Guru, Paul, Ashim, Gazit, Ehud, Segal, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-01-2018; Nature Publishing Group
• Subjects: 119/118; 14/28; 14/34; 631/45/56; 631/92/56; Aggregates; Alzheimer's disease; Fibrils; Humanities and Social Sciences; Hybrids; Hydrophobicity; Medical treatment; Molecular dynamics; multidisciplinary; Neurodegenerative diseases; Peptides; Protein folding; Proteins; Science; Science (multidisciplinary); Senile plaques; Spectroscopy; Structure-function relationships; Tau protein; Tryptophan; β-Amyloid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-18443-2

Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer’s disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau protein
in vitro
, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM. Molecular dynamics simulation of PHF6 oligomers and fibrils with the Naphthoquinone-Tryptophan hybrids provides a possible structure-function based mechanism-of-action, highlighting the role of hydrophobic interaction and hydrogen bond formation during fibril disassembly. These findings signify the effectiveness of NQTrp and Cl-NQTrp in disassembling fibrillar aggregates and may help in designing novel hybrid molecules for AD treatment.