Modeling Parkinson’s disease in yeast

Abstract

Alpha-Synuclein (α-Syn) is a protein mostly found in the presynaptic terminal of neurons in the brain. It is implicated in the neuropathology of Parkinson’s Disease (PD) to form Lewy bodies when accumulated progressively. Previous studies have shown that wild-type and 6 mutant α-Syn forms amyloid fibrils in vitro with a fast kinetics when they are C-terminally truncated. In this study, the aggregation and toxicity level of the different α-Syn was investigated in yeast. Through fluorescence microscopy and toxicity assays, I discovered that mutants A30P and G51D α-Syn show a strikingly different phenotype from the other α-Syn mutants. Unlike wild-type or other mutant α-Syn that associate with the plasma membrane, A30P, and G51D α-Syn were distributed in the cytosol. A30P and G51D α-Syn also showed alleviated toxicity in yeast. Therefore, this implies that α-Syn toxicity is likely to be related to the α-Syn lipid-binding propensity which may affect vesicle trafficking in yeast. Unlike previous in vitro studies, however, I did not observe a significant difference in the phenotype of C-terminally truncated α-Syn. Here, I confirmed that α-Syn toxicity in yeast correlates with its expression level. This study provides further insights into the contribution of α-Syn to the neuropathology of PD.