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Vol. 19, Issue 3, 1093-1103, March 2008

This Article Full Text Full Text (PDF) Supplemental Materials A correction has been published All Versions of this Article: E07-08-0827v1 E07-08-0827v2 19/3/1093    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Soper, J. H. Articles by Lee, V. M.-Y. Search for Related Content PubMed PubMed Citation Articles by Soper, J. H. Articles by Lee, V. M.-Y.

-Synuclein–induced Aggregation of Cytoplasmic Vesicles in Saccharomyces cerevisiae

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

*Center for Neurodegenerative Disease Research and Departments of Pathology and Laboratory Medicine and Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104

Submitted August 29, 2007; Revised December 12, 2007; Accepted December 20, 2007
Monitoring Editor: Jeffrey Brodsky

Aggregated -synuclein (-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 Saccharomyces cerevisiae, -syn localizes to plasma membranes and forms cytoplasmic accumulations similar to human -syn inclusions. However, the exact nature, composition, temporal evolution, and underlying mechanisms of yeast -syn accumulations and their relevance to human synucleinopathies are unknown. Here we provide ultrastructural evidence that -syn accumulations are not comprised of LB-like fibrils, but are associated with clusters of vesicles. Live-cell imaging showed -syn initially localized to the plasma membrane and subsequently formed accumulations in association with vesicles. Imaging of truncated and mutant forms of -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, -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)

Abbreviations used: -syn, -synuclein; EM, electron microscopy; ER, endoplasmic reticulum; GTPase, guanosine triphosphatase; PD, Parkinson's disease; WT, wild type.