Yeast Models in Neurodegenerative Disease Studies

Yeast species, in particular Saccharomyces cerevisiae and emerging non-conventional yeasts, have become powerful platforms to dissect the molecular basis of human neurodegenerative conditions. Their appeal lies in the conservation of core eukaryotic pathways—protein folding, quality control, trafficking and stress responses—combined with rapid growth, facile genetic manipulation and compatibility with high-throughput screening. By expressing human disease-associated proteins such as amyloid-β peptides, tau or α-synuclein in yeast, investigators have modelled fundamental steps in misfolding, aggregation and cytotoxicity. These simple eukaryotes permit genome-wide interaction studies, chemical screens for modifiers of proteotoxicity and real-time monitoring of protein aggregation or organelle dysfunction. Yeast models have illuminated how perturbations in proteostasis networks, redox balance and vesicular trafficking contribute to peptide oligomer formation, mitochondrial impairment and cell death. They also offer a cost-effective first pass for identifying candidate therapeutic molecules and biomarkers. As a bridge between biochemical assays and complex animal models, yeast research continues to generate mechanistic insights with global significance for Alzheimer’s, Parkinson’s, Huntington’s and prion diseases.

Research from Nature Portfolio

Recent studies have exploited genome-wide synthetic interaction mapping in yeast expressing the human amyloid-β42 peptide to identify modulators of toxicity. A screen revealed that increased cellular levels of flavin mononucleotide (FMN), produced by riboflavin kinase, mitigate Aβ42-induced growth defects. FMN supplementation was found to lower misfolded protein load, enhance NADH/NAD+ and NADPH/NADP+ ratios and bolster resistance to oxidative stress. These metabolic shifts also reduced toxicity of other aggregation-prone proteins, including expanded glutamine tracts and α-synuclein, underscoring a conserved FMN-dependent pathway. This work offers a proof of principle for using metabolic cofactor supplementation to rewire proteostasis and attenuate neurodegeneration-related cytotoxicity.

Yeast Models in Neurodegenerative Disease Studies publication trend

The graph below shows the total number of articles in yeast models in neurodegenerative disease studies across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid-β (Aβ): A peptide derived from amyloid precursor protein that aggregates into oligomers and fibrils implicated in Alzheimer’s disease.

Tau protein: A microtubule-associated protein in neurons which becomes hyperphosphorylated and aggregates in tauopathies.

Proteostasis: The ensemble of cellular pathways responsible for protein folding, quality control, trafficking and degradation.

Prion: A misfolded protein capable of inducing conformational change and aggregation in native counterparts, contributing to transmissible proteopathies.

Oxidative stress: A condition arising from an imbalance between reactive oxygen species production and antioxidant defences, affecting protein and organelle integrity.

References

1. Effects of heterologous human tau protein expression in yeast models of proteotoxic stress response. CNS Neuroscience & Therapeutics (2023).
2. How Big Is the Yeast Prion Universe?. International Journal of Molecular Sciences (2023).
3. FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism. Nature Communications (2020).
4. Alzheimer’s Disease: Significant Benefit from the Yeast-Based Models. International Journal of Molecular Sciences (2023).