YGR198w (YPP1) targets A30P α-synuclein to the vacuole for degradation

U sing a genetic screen we discovered that YGR198w ( named YPP1), which is an essential Saccharomyces cerevisiae gene of unknown function, suppresses the toxicity of an alpha-synuclein (alpha-syn) mutant ( A30P) that is associated with early onset Parkinson's disease. Here, we show that YPP1 suppresses lethality of A30P, but not of wild-type alpha-syn or the A53T mutant. The Ypp1 protein, when overexpressed, drives each of the three alpha-syns into vesicles that bud off the plasma membrane, but only A30P-containing vesicles traffick to and merge with the vacuole, where A30P is proteolytically degraded. We show that Ypp1p binds to A30P but not the other two alpha-syns; that YPP1 interacts with genes involved in endocytosis/ actin dynamics ( SLA1, SLA2, and END3), protein sorting ( class E vps), and vesicle- vacuole fusion ( MON1 and CCZ1) to dispose of A30P; and that YPP1 also participates in pheromone- triggered receptor- mediated endocytosis. Our data reveal that YPP1 mediates the trafficking of A30P to the vacuole via the endocytic pathway.