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Molecular Determinant of α-Synuclein Pathotoxicity in Yeast Models

Parkinson disease (PD) is an incurable neurodegenerative disorder linked to the misfolding and aggregation of α-synuclein protein in dying neurons. Several molecular features of α-synuclein that appear to contribute to its properties are the familial mutant E46K, serine phosphorylation, and hydrophobic residues, but their exact role is unclear. I used two yeast models to examine how the E46K mutation, phosphorylation, and alanine-76 impact the properties of α-synuclein. My thesis research revealed three important findings: 1) The E46K familial mutation bound membranes in budding yeast, aggregated in fission yeast, and induced toxicity in a strain-specific manner. 2) Phosphorylation of α-synuclein influenced the protein’s ability to aggregate, but the phosphorylation state did not determine toxicity in yeast. 3) Alanine-76 decreased membrane binding in budding yeast and aggregation in fission yeast. This thesis provided multiple lines of insight into the molecular determinants of α-synuclein toxicity. An increased understanding of α-synuclein’s pathotoxic properties could lead to more effective therapeutic strategies.