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doi:10.1534/genetics.104.035493
A more recent version of this article appeared on May 1, 2005.
REGULAR RESEARCH PAPERS |
Alpha-Synuclein Targets the Plasma Membrane via the Secretory Pathway and Induces Toxicity in Yeast
Cheryl Dixon 1, Neal Mathias 1, Richard M. Zweig 1, Donnie A. Davis 1 and David S Gross 1*
1 Louisiana State University HSC
* To whom correspondence should be addressed. E-mail: dgross{at}lsuhsc.edu.
Submitted on August 28, 2004
Revised on October 16, 2004
Accepted on 25 January 2005
A pathological feature of Parkinson's disease is the presence of Lewy bodies within selectively vulnerable neurons. These are ubiquitinated cytoplasmic inclusions containing alpha-synuclein, an abundant protein normally associated with pre-synaptic terminals. Point mutations in the alpha-synuclein gene (A30P and A53T), as well as triplication of the wild-type (WT) locus, have been linked to autosomal dominant Parkinson's. How these alterations might contribute to disease progression is unclear. Using the genetically tractable yeast Saccharomyces cerevisiae as a model system, we find that both the WT and A53T isoforms of alpha-synuclein initially localize to the plasma membrane, to which they are delivered via the classical secretory pathway. In contrast, the A30P mutant disperses within the cytoplasm, does not associate with the plasma membrane, and its intracellular distribution is unaffected by mutations in the secretory pathway. When their expression is elevated, WT and A53T, but not A30P, are toxic to cells. At moderate levels of expression, WT and A53T induce the heat shock response and are toxic to cells bearing mutations in the 20S proteasome. Our results reveal a link between plasma membrane targeting of alpha-synuclein and its toxicity in yeast, and reveal a role for the quality control (QC) system in the cel's effort to deal with this natively unfolded protein.
Key Words: Parkinson's Disease, Saccharomyces cerevisiae, heat shock response, proteasome, sec mutants
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