Abstract 1146 Insight into Synucleinopathies: Comparative Evaluation of Wild-Type α-, β-, and -Synucleins in a Yeast Model

Synucleinopathies are a group of neurodegenerative disorders linked with the misfolding and aggregation of ⍺-synuclein, the most well-known among them being Parkinson's disease (PD). ⍺-Synuclein belongs to a larger family of proteins that include β- and γ-synuclein. Mutant forms (P123H and V70M) of β-synuclein have been shown to cause Dementia with Lewy Bodies (DLB).However, the extent to which β- and γ-synuclein are neurotoxic is still highly understudied compared to ⍺-synuclein. While specific alterations in cellular environments (including nitrative stress, lysosomal degradation, mitochondrial dysfunction) and post-translational modifications alter the toxicity and aggregation of α-synuclein, less is known of their impacts on β- and γ-synuclein. Here, we used our lab's budding yeast (Saccharomyces cerevisiae) model to comparatively evaluate these three wildtype synucleins and explore their pathological potential through the assessment of toxicity, localization, and expression. We report that: 1) Both wildtype ⍺- and β-synuclein are differentially toxic in control yeast strains, whereas γ-synuclein is non-toxic. 2) Expression levels of these proteins are tied to extent of aggregation and cytotoxicity observed. 3) Toxicity potential of all synucleins are impacted to varying degrees by specific synucleinopathy-related altered cellular environments in genetically altered yeast strains. 4) β-synuclein, when expressed in budding yeast, displays a higher molecular weight than expected. This study adds to a growing body of research exploring disease association of the synuclein family of proteins and illustrates the importance of further evaluation of β-synuclein's role in neurodegeneration. We would like to thank Parkinson's Foundation and Nu Rho Psi to help fund this research.