Aggregate Clearance of -Synuclein in Saccharomyces cerevisiae Depends More on Autophagosome and Vacuole Function Than on the Proteasome*□S

Background: The hallmark of Parkinson disease is -synuclein aggregation, whose cytotoxic effects are reproducible in yeast. Results: -Synuclein aggregate clearance is impaired by vacuolar protease inhibitor PMSF but not by proteasome inhibitor MG132. Conclusion: Yeast recovers from -synuclein-induced toxicity by clearing aggregates via autophagy and vacuolar pathways. Significance: The data provide insight into the mechanisms used by yeast cells to clear toxic aggregated proteins. Parkinson disease is the second most common neurodegen-erative disease. The molecular hallmark is the accumulation of proteinaceous inclusions termed Lewy bodies containing mis-folded and aggregated -synuclein. The molecular mechanism of clearance of -synuclein aggregates was addressed using the bakers ’ yeast Saccharomyces cerevisiae as the model. Overex-pression of wild type -synuclein or the genetic variant A53T integrated into one genomic locus resulted in a gene copy-de-pendent manner in cytoplasmic proteinaceous inclusions remi