Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and α-synuclein plays an important role in its development. Using the genetically tractable Saccharomyces cerevisiae as a model system, the phenotypic repercussions and potential mechanisms of α-synuclein-induced cytotoxicity are characterized through modulating its expression level and other cellular factors. Aggregation-induced toxicity is more dramatic upon elevated expression of α-synuclein than that induced at moderate levels of expression. The induced toxicity is also enhanced by reagents such as dimethyl sulfoxide, which increase intracellular levels of phospholipid and membrane, as well as ferrous ions and hydrogen peroxide, both of which cause oxidative stresses in yeast cells. In contrast, over-expression of yeast homologue of human chaperone DJ-1, YDR533C, markedly alleviate the inhibition of growth afflicted by exogenous expression of α-synuclein. Taken together, the data presented suggest a role for protein folding machinery together with quality control system in dealing with the aggregation of α-synuclein.