The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies

详细信息    查看全文

• 作者：Manuela Leri^a ; ¹ ; ^{manuela.leri@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Daniele Nosi^b ; ¹ ; ^{daniele.nosi@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Antonino Natalello^c ; ^{antonino.natalello@unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Riccardo Porcari^e ; ^{r.porcari@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Matteo Ramazzotti^a ; ^{matteo.ramazzotti@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Fabrizio Chiti^a ; ^g ; ^{fabrizio.chiti@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Vittorio Bellotti^e ; ^f ; ^{v.bellotti@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Silvia Maria Doglia^c ; ^d ; ^{silviamaria.doglia@unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Massimo Stefani^a ; ^f ; ^{massimo.stefani@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Monica Bucciantini^a ; ^f ; ^{monica.bucciantini@unifi.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Transthyretin ; Oleuropein aglycone ; Amyloid ; FAP ; FAC
• 刊名：Journal of Nutritional Biochemistry
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：30
• 期：Complete
• 页码：153-166
• 全文大小：3054 K

文摘

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.