Reference: Liang J, et al. (2008) Novel suppressors of alpha-synuclein toxicity identified using yeast. Hum Mol Genet 17(23):3784-95

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Abstract


The mechanism by which the Parkinson's disease-related protein alpha-synuclein (alpha-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from alpha-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing alpha-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking, and the response to stress were identified. Five of the forty genes-ENT3, IDP3, JEM1, ARG2, and HSP82-ranked highest in their ability to block alpha-syn-induced reactive oxygen species (ROS) accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of alpha-syn as judged by growth defects compared to wild-type cells expressing alpha-syn, which indicates that these genes protect cells from alpha-syn. Strikingly, four of the five genes are specific for alpha-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that alpha-syn causes toxicity to cells via a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes alpha-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of alpha-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans.

Reference Type
Journal Article
Authors
Liang J, Clark-Dixon C, Wang S, Flower TR, Williams-Hart T, Zweig R, Robinson LC, Tatchell K, Witt SN
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