Characterization of α-synuclein aggregation and synergistic toxicity with protein tau in yeast

Abstract

A yeast model was generated to study the mechanisms and phenotypical repercussions of expression of α-synuclein as well as the coexpression of protein tau. The data show that aggregation of α-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 α-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 α-synuclein occurs via autophagy and proteasomes and that aggregation of α-synuclein disturbs endocytosis. Reminiscent of observations in double-transgenic mice, coexpression of α-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 α-synuclein aggregation and cytotoxicity, and offer great potential for defining the underlying mechanisms of toxicity and synergistic actions of α-synuclein and protein tau. © 2005 FEBS.