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MBC in Press, published online ahead of print January 9, 2008
Mol. Biol. Cell 10.1091/mbc.E07-08-0827

A more recent version of this article appeared on March 1, 2008 Originally published as MBC in Press, 10.1091/mbc.E07-08-0827 on January 2, 2008
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Submitted on August 29, 2007
Revised on December 12, 2007
Accepted on December 20, 2007

{alpha}-Synuclein Induced Aggregation of Cytoplasmic Vesicles in Saccharomyces cerevisiae

James H. Soper,*{dagger} Subhojit Roy,*{dagger} Anna Stieber,*{dagger} Eliza Lee,*{dagger} Robert B. Wilson,{dagger} John Q. Trojanowski,*{dagger} Christopher G. Burd,{ddagger} and Virginia M.-Y. Lee*{dagger}

*Center for Neurodegenerative Disease Research, {dagger}Department of Pathology and Laboratory Medicine, {ddagger}Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104

Monitoring Editor: Jeffrey Brodsky

Aggregated {alpha}-synuclein ({alpha}-syn) fibrils form Lewy bodies (LBs), the signature lesions of Parkinson’s disease (PD) and related synucleinopathies, but the pathogenesis and neurodegenerative effects of LBs remain enigmatic. Recent studies have shown that when overexpressed in S. cerevisiae, {alpha}-syn localizes to plasma membranes and forms cytoplasmic accumulations similar to human {alpha}-syn inclusions. However, the exact nature, composition, temporal evolution and underlying mechanisms of yeast {alpha}-syn accumulations and their relevance to human synucleinopathies are unknown. Here we provide ultrastructural evidence that {alpha}-syn accumulations are not comprised of LB-like fibrils, but are associated with clusters of vesicles. Live-cell imaging showed {alpha}-syn initially localized to the plasma membrane, and subsequently formed accumulations in association with vesicles. Imaging of truncated and mutant forms of {alpha}-syn revealed the molecular determinants and vesicular trafficking pathways underlying this pathological process. Because vesicular clustering is also found in LB containing neurons of PD brains, {alpha}-syn mediated vesicular accumulation in yeast represents a model system to study specific aspects of neurodegeneration in PD and related synucleinopathies.

Address correspondence to: Virginia M.-Y. Lee (vmylee{at}mail.med.upenn.edu)






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