title: The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies.
abstract: Transthyretin (TTR) is involved in a subset of familial or sporadic amyloid diseases including senile systemic amyloidosis (SSA), familial amyloid polyneuropathy and cardiomyopathy (FAP/FAC) for which no effective therapy has been found yet. These conditions are characterized by extracellular deposits primarily found in the heart parenchyma and in peripheral nerves whose main component are amyloid fibrils, presently considered the main culprits of cell sufferance. The latter are polymeric assemblies grown from misfolded TTR, either wt or carrying one out of many identified mutations. The recent introduction in the clinical practice of synthetic TTR-stabilizing molecules that reduce protein aggregation provides the rationale to search natural effective molecules able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favoring the growth of harmless aggregates. Here we carried out an in depth biophysical and morphological study on the molecular features of the aggregation of wt- and L55P-TTR involved in SSA or FAP/FAC, respectively, and on the interference with fibril aggregation, stability and toxicity to cardiac HL-1 cells to demonstrate the ability of Oleuropein aglycone (OleA), the main phenolic component of the extra virgin olive oil. We describe the molecular basis of such interference and the resulting reduction of TTR amyloid aggregate cytotoxicity. Our data offer the possibility to validate and optimize the use of OleA or its molecular scaffold to rationally design promising drugs against TTR-related pathologies that could enter a clinical experimental phase.
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio"- Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy. Electronic address: manuela.leri@unifi.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Leri
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica - Università degli Studi di Firenze, Largo Brambilla 3, 50134, Firenze, Italy. Electronic address: daniele.nosi@unifi.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Nosi
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, Piazza della Scienza 2, 20126, Milano, Italy. Electronic address: antonino.natalello@unimib.it.
authors.forename: Antonino
authors.initials: A
authors.lastname: Natalello
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus University College London, NW3 2PF, London, UK. Electronic address: r.porcari@ucl.ac.uk.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio"- Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy. Electronic address: matteo.ramazzotti@unifi.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Ramazzotti
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio"- Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy; Centro Interuniversitario per lo Studio delle Malattie Neurodegenerative (CIMN), 50134, Firenze, Italy. Electronic address: fabrizio.chiti@unifi.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus University College London, NW3 2PF, London, UK; Dipartimento di Medicina Molecolare, Istituto di Biochimica, Università degli Studi di Pavia, 27100, Pavia, Italy. Electronic address: v.bellotti@ucl.ac.uk.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, Piazza della Scienza 2, 20126, Milano, Italy; Dipartimento di Fisica G. Occhialini, Università degli Studi di Milano-Bicocca, Piazza della Scienza 3, 20126, Milano, Italy. Electronic address: silviamaria.doglia@unimib.it.
authors.forename: Silvia Maria
authors.initials: SM
authors.lastname: Doglia
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio"- Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy; Dipartimento di Medicina Molecolare, Istituto di Biochimica, Università degli Studi di Pavia, 27100, Pavia, Italy. Electronic address: massimo.stefani@unifi.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Stefani
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio"- Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy; Dipartimento di Medicina Molecolare, Istituto di Biochimica, Università degli Studi di Pavia, 27100, Pavia, Italy. Electronic address: monica.bucciantini@unifi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Bucciantini
mesh_terms: D000818:Animals; D002460:Cell Line; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology*; D051379:Mice; D011228:Prealbumin / Q000037:antagonists & inhibitors*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D057888:Iridoid Glucosides; D039823:Iridoids; D011228:Prealbumin; C002769:oleuropein
keywords: Amyloid; FAC; FAP; Oleuropein aglycone; Transthyretin