A Novel Yeast model for tyrosine accumulation and self-assembly

The formation of amyloid assemblies has been associated with several major human maladies, mostly neurodegenerative disorders. For over a decade, the self-assembly process was attributed only to proteins and polypeptides. Yet, by utilizing a reductionist approach, using shorter amyloidogenic building block, it was demonstrated in our lab that metabolites, such as amino acids and nucleobases, can also from typical amyloidal assemblies. As a result of inborn mutations in single genes encoding for metabolic enzymes these metabolites can accumulate and might be associated with the pathology of several inborn error of metabolism (IEM) disorders. Most of the studies regarding metabolite amyloid-like structures were conducted so far only in vitro. Recently, a yeast model for adenine accumulation and self-assembly that recapitulates adenine IEM disorders was established. Furthermore, the intracellular assembly of adenine amyloid-like structures has been demonstrated using this yeast model. Herein, we established an additional model for tyrosine accumulation and self-assembly in yeast. By using strain partially blocked in the shikimate pathway, we observed non-linear dose-dependent growth inhibition upon tyrosine feeding which was shown to be associated with increased intracellular accumulation of tyrosine. Staining with amyloid-specific dye demonstrated the presence of tyrosine amyloid-like assemblies. Moreover, treatment with epigallocatechin gallate (EGCG) resulted in a significant reduction in the formation of the toxic tyrosine amyloid-like assemblies which further supports the notion that toxicity is triggered by tyrosine assemblies. This model can provide insights into the mechanism of metabolite self-assembly in tyrosinemia and a platform to discover disease-modifying therapeutic avenues.