title: YGR198w (YPP1) targets A30P alpha-synuclein to the vacuole for degradation.
abstract: Using 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Flower
authors.forename: Cheryl
authors.initials: C
authors.lastname: Clark-Dixon
authors.forename: Cheynita
authors.initials: C
authors.lastname: Metoyer
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Runhua
authors.initials: R
authors.lastname: Shi
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Zhang
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Witt
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004705:Endocytosis; D010300:Parkinson Disease; D010447:Peptide Hydrolases / Q000378:metabolism; D021381:Protein Transport; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D029701:Saccharomyces cerevisiae Proteins; C522639:YPP1 protein, S cerevisiae; D051844:alpha-Synuclein; D010447:Peptide Hydrolases