FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism

Xin Chen, Boyang Ji, Xinxin Hao, Xiaowei Li, Frederik Eisele, Thomas Nyström and Dina Petranovic ()
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Xin Chen: Chalmers University of Technology
Boyang Ji: Chalmers University of Technology
Xinxin Hao: University of Gothenburg
Xiaowei Li: Chalmers University of Technology
Frederik Eisele: University of Gothenburg
Thomas Nyström: University of Gothenburg
Dina Petranovic: Chalmers University of Technology

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Alzheimer’s disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-β peptides (Aβ) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of Aβ42, using yeast as the model organism. We find that FMN1, the gene encoding riboflavin kinase, and its metabolic product flavin mononucleotide (FMN) reduce Aβ42 toxicity. Classic experimental analyses combined with RNAseq show the effects of FMN supplementation to include reducing misfolded protein load, altering cellular metabolism, increasing NADH/(NADH + NAD+) and NADPH/(NADPH + NADP+) ratios and increasing resistance to oxidative stress. Additionally, FMN supplementation modifies Htt103QP toxicity and α-synuclein toxicity in the humanized yeast. Our findings offer insights for reducing cytotoxicity of Aβ42, and potentially other misfolded proteins, via FMN-dependent cellular pathways.

Date: 2020
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DOI: 10.1038/s41467-020-14525-4

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