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Human Molecular Genetics Advance Access originally published online on September 4, 2008
Human Molecular Genetics 2008 17(23):3784-3795; doi:10.1093/hmg/ddn276
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Novel suppressors of {alpha}-synuclein toxicity identified using yeast

Jun Liang1, Cheryl Clark-Dixon1, Shaoxiao Wang1, Todd R. Flower1, Tara Williams-Hart3, Richard Zweig2, Lucy C. Robinson1, Kelly Tatchell1 and Stephan N. Witt1,*

1 Department of Biochemistry and Molecular Biology 2 Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA 3 Department of Biological Sciences, Louisiana State University in Shreveport, One University Place, LA 71115, USA

* To whom correspondence should be addressed. Tel: +1 3186757891; Fax: +1 3186755180; Email: switt1{at}lsuhsc.edu

Received May 29, 2008; Revised August 9, 2008; Accepted August 29, 2008

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 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 with 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 through 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.


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