Characterization of alpha-synuclein aggregation and synergistic toxicity with protein tau in yeast.
A yeast model was generated to study the mechanisms and phenotypical repercussions of expression of alpha-synuclein as well as the coexpression of protein tau. The data show that aggregation of alpha-synuclein is a nucleation-elongation process initiated at the plasma membrane. Aggregation is consistently enhanced by dimethyl sulfoxide, which is known to increase the level of phospholipids and membranes in yeast cells. Aggregation of alpha-synuclein was also triggered by treatment of the yeast cells with ferrous ions, which are known to increase oxidative stress. In addition, data are presented in support of the hypothesis that degradation of alpha-synuclein occurs via autophagy and proteasomes and that aggregation of alpha-synuclein disturbs endocytosis. Reminiscent of observations in double-transgenic mice, coexpression of alpha-synuclein and protein tau in yeast cells is synergistically toxic, as exemplified by inhibition of proliferation. Taken together, the data show that these yeast models recapitulate major aspects of alpha-synuclein aggregation and cytotoxicity, and offer great potential for defining the underlying mechanisms of toxicity and synergistic actions of alpha-synuclein and protein tau.
Zabrocki
Piotr
P
Functional Biology, Katholieke Universiteit Leuven, Belgium.
Pellens
Klaartje
K
Vanhelmont
Thomas
T
Vandebroek
Tom
T
Griffioen
Gerard
G
Wera
Stefaan
S
Van Leuven
Fred
F
Winderickx
Joris
J
D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004705:Endocytosis / Q000502:physiology; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins / Q000378:metabolism
D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D029701:Saccharomyces cerevisiae Proteins; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex; D004121:Dimethyl Sulfoxide