Alpha-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae.
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.
Soper
James H
JH
Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Roy
Subhojit
S
Stieber
Anna
A
Lee
Eliza
E
Wilson
Robert B
RB
Trojanowski
John Q
JQ
Burd
Christopher G
CG
Lee
Virginia M-Y
VM
D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D022162:Cytoplasmic Vesicles / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000648:ultrastructure; D010300:Parkinson Disease / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D022142:Secretory Vesicles / Q000378:metabolism / Q000648:ultrastructure; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020691:rab GTP-Binding Proteins