Does α-Synuclein use Endocytosis as a Route for Degradation by the Lysosome?

Parkinson’s disease (PD) is an incurable fatal brain disorder linked to three disease-related properties that result from α-synuclein accumulation: its misfolding, aggregation, and cellular toxicity. Accelerating αsynuclein degradation might provide therapy by reducing its accumulation. We tested if the lysosome degrades α-synuclein by a specific route, endocytosis, in a budding yeast model for PD. Specifically, we evaluated if α-synuclein accumulation, aggregation, and toxicity worsened in seven yeast strains that had individual gene deletions, which control specific steps within endocytosis. We report three significant findings. Firstly, all seven genes affected at least one α-synuclein PD-related property, thus providing accumulating genetic evidence for the endosome pathway as a regulator of α-synuclein degradation. Secondly, each gene affected α-synuclein properties to different extents, suggesting substrate specificity for endocytosis steps. Lastly, none of the genes contributed additional α-synuclein-dependent toxicity. Together, our data suggests that α-synuclein is degraded by the lysosome using the endocytosis route. Introduction