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PMID: 18172022 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Alpha-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae.

Molecular biology of the cell ·Vol. 19 ·No. 3 ·2008-03-00 ·Pages 1093-103

Soper JH, Roy S, Stieber A, Lee E, Wilson RB, Trojanowski JQ, Burd CG, Lee VM

Abstract

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 Saccharomyces 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.

MeSH Terms
Cell Membrane/metabolism,ultrastructure Cytoplasmic Vesicles/enzymology,metabolism,ultrastructure Endoplasmic Reticulum/metabolism,ultrastructure Endosomes/metabolism,ultrastructure Golgi Apparatus/metabolism,ultrastructure Green Fluorescent Proteins/metabolism Humans Lewy Bodies/metabolism,ultrastructure Parkinson Disease/metabolism Protein Structure, Tertiary Recombinant Fusion Proteins/metabolism Saccharomyces cerevisiae/cytology,metabolism,ultrastructure Secretory Vesicles/metabolism,ultrastructure Vacuoles/metabolism,ultrastructure alpha-Synuclein/chemistry,metabolism rab GTP-Binding Proteins/metabolism
Chemicals
Recombinant Fusion Proteins alpha-Synuclein enhanced green fluorescent protein Green Fluorescent Proteins rab GTP-Binding Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Soper James H
Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Roy Subhojit
Stieber Anna
Lee Eliza
Wilson Robert B
Trojanowski John Q
Burd Christopher G
Lee Virginia M-Y
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.e07-08-0827
Published
2008-03-00
Epub
2008-00-02
Pages
1093-103
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2262993
Subset
IM
Grants
NIA NIH HHS · AG-P01-09215 · United States
NIGMS NIH HHS · GM T32 07229 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1091/mbc.e07-08-0827 PMC Full Text View journal details
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