tailieunhanh - Báo cáo khoa học: Characterization of a-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 a-synuclein as well as the coexpression of protein tau. The data show that aggregation ofa-synuclein is a nucleation– elongation process initiated at the plasma membrane. Aggregation is con-sistently enhanced by dimethyl sulfoxide, which is known to increase the level of phospholipids and membranes in yeast cells. | iFEBS Journal Characterization of a-synuclein aggregation and synergistic toxicity with protein tau in yeast Piotr Zabrocki1 Klaartje Pellens1 Thomas Vanhelmont1 Tom Vandebroek2 Gerard Griffioen3 Stefaan Wera3 Fred Van Leuven2 and Joris Winderickx1 1 FunctionalBiology Katholieke Universiteit Leuven Belgium 2 LEGT_EGG Katholieke Universiteit Leuven Belgium 3 . reMYND Leuven Belgium Keywords Alzheimer s disease Parkinson s disease Tau yeast a-synuclein Correspondence J. Winderickx FunctionalBiology Kasteelpark Arenberg 31 B-3001 Leuven-Heverlee Belgium Fax 32 16 321967 Tel 32 16 321516 E-mail Received 22 November 2004 revised 12 January 2005 accepted 18 January 2005 doi A yeast model was generated to study the mechanisms and phenotypical repercussions of expression of a-synuclein as well as the coexpression of protein tau. The data show that aggregation of a-synuclein is a nucleationelongation 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 a-synu-clein 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 a-synuclein occurs via autophagy and proteasomes and that aggregation of a-synuclein disturbs endocytosis. Reminiscent of observations in double-transgenic mice coexpression of a-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 a-synuclein aggregation and cytotoxicity and offer great potential for defining the underlying mechanisms of toxicity and synergistic actions of a-synuclein and protein tau. Aberrant aggregation of specific proteins is a common .