Parkinson's disease (PD) is an incurable neurodegenerative disease resulting from dopaminergic neuronal death in the substantia nigra, likely due to the misfolding and aggregation of the protein alpha-synuclein. A major hypothesis is that increasing the degradation of alpha-synuclein reduces toxicity and aggregation. The lysosome is pharmacologically implicated in the degradation of alpha-synuclein. Macroautophagy (autophagy), a highly conserved catabolic process in eukaryotes, is a major route to the lysosome. The genetic link between PD and autophagy is currently tenuous and a subject of intense research in our lab. In this study, we hypothesized that basal autophagy would protect cells from a-synuclein toxicity, and tested this by genetically inhibiting the nucleation and fusion steps of autophagy in a budding yeast model. We assessed alpha-synuclein's pathotoxicity linked properties (accumulation, aggregation and toxicity) in yeast autophagy gene (ATG) knockout strains needed for nucleation (ATG11 and ATG13) and two needed for fusion (VAM3 and VAM7). We are among the first to report that autophagy fusion step genes can regulate several of alpha-synuclein's PD-related properties. Also, we found that the absence of any of these four genes altered alpha-synuclein localization, while three affected its accumulation, and none induced cellular toxicity. These new results support accumulating data from our lab for the role for autophagy in alpha-synuclein regulation, but will be further aided by completion of analysis of autophagy genes yet to be studied.
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