Characterization of Familial Mutants and Splice Variants of Parkinson’s Disease Pro- tein α- Synuclein in Yeast Models

The misfolding of the protein α-synuclein is a major contributor to Parkinson’s disease (PD). Three mutations (A53T, A30P and E46K) cause familial PD, and three newly discovered spliced variant forms of the protein (syn-126, syn-112, and syn-98) are also found in many PD patients. Little is known about whether these familial mutants can influence each other’s contributing properties and whether the spliced variants are protective or harmful. Each familial mutant distinctively affects α-synuclein’s cellular localization, aggregation, and toxicity. For my thesis, I first tested the hypothesis that all three familial mutants equally influence a-synuclein’s pathological contributions in yeast models and found unexpected support for the dominance of the A30P mutant over E46K and A53T, shedding new light on A30P’s influence of a-synuclein’s conformation. Using polymerase chain reaction-based strategies, I have also made significant progress in creating the three spliced-variants for future evaluation in yeasts to assess their contributions to PD.