Evaluating α-Synuclein’s Interaction with Cellular Phospholipids and Potential Toxicity in Yeast Models for Parkinson’s Disease

Parkinson’s disease is a progressive neurodegenerative disease caused by the death of midbrain dopaminergic neurons. The misfolding and aggregation of α-synuclein plays a ruinous role in this disease, but how the protein becomes toxic is unclear. Using yeasts as model organisms for studying α-synuclein properties, our study explores the hypothesis that α-synuclein toxicity depends on plasma membrane phospholipid binding. First, using a chemical approach, we induced phospholipid synthesis in both fission and budding yeast with dimethyl sulfoxide (DMSO), a known inducer [1]. Instead of regulating α-synuclein-dependent toxicity, DMSO unexpectedly exerted its own toxicity in both yeasts, in addition to inducing a lethal morphology defect in budding yeast. Moreover, instead of inducing plasma membrane localization of α-synuclein in either yeast, DMSO altered α-synuclein localization in both yeasts into as-yet unidentified cytoplasmic structures. We speculate that some of these structures may be internal, membrane bound organelles. To test for membrane phospholipid binding specifically, α-synuclein localization was analyzed in a phosphatidylserine-deficient budding yeast strain. We observed no loss of plasma membrane localization, suggesting that other phospholipids may regulate such specificity to α-synuclein. Together, these related studies illustrate the usefulness of yeasts in evaluating genetic and environmental factors that regulate α-synuclein toxicity linked to Parkinson’s disease