FMN reduces Amyloid-\u03b2 toxicity in yeast by regulating redox status and cellular metabolism

Xin Chen,Frederik Eisele,Xinxin Hao,Boyang Ji,Dina Petranovic,Thomas Nyström,Xiaowei Li

doi:10.1038/s41467-020-14525-4

Xin Chen, Frederik Eisele + Show 5 more

Open Access

https://doi.org/10.1038/s41467-020-14525-4

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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.

Highlights

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
The query strains were mated with the yeast deletion mutant library to generate two arrays, where each deletion strain on the array was combined with either the control or Aβ42 expression
The results showed that FMN1 mRNA levels were significantly increased in the post-diauxic shift (PD) and stationary phases (SP) cells compared to exponentially growing cells (EX) in both Aβ42 and control strains (p-adj < 0.05, Fig. 3c)

Summary

Introduction

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. Alzheimer’s disease (AD) is the most common neurodegenerative disorder in aging populations It is categorized as a protein misfolding, or protein conformational disease due to the accumulation of misfolded amyloid-β (Aβ) peptides, which are defined as one of its principal hallmarks[1]. Due to the strong conservation of protein quality control systems among eukaryotic cells, the yeast Saccharomyces cerevisiae has become a powerful model organism to study misfolded proteins and their implication in human pathologies. Aβ peptides are generated through the sequential cleavage of the amyloid precursor protein (APP)[16] by BACE and γ-secretase[17], which occurs in the secretory pathway and endocytic pathway in neurons[18]. Aβ42 peptides subsequently form more oligomers relative to Aβ40 and exhibit an increased cellular toxicity in yeast[19,20]

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