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, Dina Petranovic

Journal: Nature communications 2020;11(1):867

PMID: 32054832

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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.

Address: Division of Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, SE41296, Gothenburg, Sweden.; Novo Nordisk Foundation Center for Biosustainability, Chalmers University of Technology, SE41296, Gothenburg, Sweden.; Institute for Biomedicine, Sahlgrenska Academy, Centre for Ageing and Health-AgeCap, University of Gothenburg, SE40530, Gothenburg, Sweden.; Division of Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, SE41296, Gothenburg, Sweden. [email protected].; Novo Nordisk Foundation Center for Biosustainability, Chalmers University of Technology, SE41296, Gothenburg, Sweden. [email protected].

DOI: 10.1038/s41467-020-14525-4

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MeSH Terms: Alzheimer Disease, Amyloid beta-Peptides, Flavin Mononucleotide, Genes, Synthetic, Genome, Fungal, Humans, Huntingtin Protein, Models, Genetic, Mutation, Oxidation-Reduction, Oxidoreductases, Peptide Fragments, Phosphotransferases (Alcohol Group Acceptor), Protein Folding, Proteolysis, RNA-Seq, Riboflavin, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, alpha-Synuclein