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 and Ehud Gazit ()
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Dana Laor: Tel Aviv University
Dorin Sade: Tel Aviv University
Shira Shaham-Niv: Tel Aviv University
Dor Zaguri: Tel Aviv University
Myra Gartner: Tel Aviv University
Vasantha Basavalingappa: Tel Aviv University
Avi Raveh: Tel Aviv University
Edward Pichinuk: Tel Aviv University
Hamutal Engel: Tel Aviv University
Keita Iwasaki: Shimane University
Tatsuyuki Yamamoto: Shimane University
Hemanth Noothalapati: Shimane University
Ehud Gazit: Tel Aviv University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07966-5

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