2. Academic Validation
  3. Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids

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

  • Sci Rep. 2018 Jan 8;8(1):71. doi: 10.1038/s41598-017-18443-2.
V Guru KrishnaKumar 1 2,  Ashim Paul 1,  Ehud Gazit 3 4,  Daniel Segal 5 6
Affiliations

Affiliations

  • 1 Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel.
  • 2 Department of Biological Engineering, Indian Institute of Technology, Gandhinagar, Palaj, Gandhinagar, Gujarat, 382355, India.
  • 3 Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel. ehudg@post.tau.ac.il.
  • 4 Department of Materials Science and Engineering Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel. ehudg@post.tau.ac.il.
  • 5 Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel. dsegal@post.tau.ac.il.
  • 6 Interdisciplinary Sagol School of Neurosciences, Tel-Aviv University, Tel Aviv, 69978, Israel. dsegal@post.tau.ac.il.
PMID: 29311706 DOI: 10.1038/s41598-017-18443-2
Abstract

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.

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