Fibril formation and therapeutic targeting of amyloid-like structures in a yeast model of adenine accumulation

Dana Laor, Dorin Sade, Shira Shaham-Niv, Dor Zaguri, Myra Gartner, Vasantha Basavalingappa, Avi Raveh, Edward Pichinuk, Hamutal Engel, Keita Iwasaki, Tatsuyuki Yamamoto, Hemanth Noothalapati, Ehud Gazit

Research output: Contribution to journalArticlepeer-review

Abstract

The extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders. However, a direct demonstration of the assembly of metabolite amyloid-like structures has so far been provided only in vitro. Here, we established an in vivo model of adenine self-assembly in yeast, in which toxicity is associated with intracellular accumulation of the metabolite. Using a strain blocked in the enzymatic pathway downstream to adenine, we observed a non-linear dose-dependent growth inhibition. Both the staining with an indicative amyloid dye and anti-adenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels. Treatment with a polyphenol inhibitor reduced the occurrence of amyloid-like structures while not affecting the dramatic increase in intracellular adenine concentration, resulting in inhibition of cytotoxicity, further supporting the notion that toxicity is triggered by adenine assemblies.

Original languageEnglish
Article number62
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

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