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Published online June 18, 2007
doi:10.1083/jcb.200610071
The Journal of Cell Biology, Vol. 177, No. 6, 1091-1104
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Flower et al.
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Article

YGR198w (YPP1) targets A30P {alpha}-synuclein to the vacuole for degradation



Todd R. Flower1, Cheryl Clark-Dixon1, Cheynita Metoyer1, Hui Yang3, Runhua Shi2, Zhaojie Zhang3, and Stephan N. Witt1

1 Department of Biochemistry and Molecular Biology, and 2 Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71130
3 Microscope Core Facility, Department 3166, University of Wyoming, Laramie, WY 82071

Correspondence to Stephan N. Witt: switt1{at}lsuhsc.edu

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.

Abbreviations used in this paper: {alpha}-syn, {alpha}-synuclein; RME, receptor-mediated endocytosis; ROS, reactive oxygen species; WT, wild-type.


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