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Experimental Genetics Group
New trends in Alzheimer and Parkinson related disorders: ADPD 2005. Vandebroek T1, Terwel D1, Vanhelmont T2, Winderickx J2, Van Leuven F1. 1Experimental Genetics Group, K.U.Leuven, Leuven, Belgium. 2Functional Biology, Katholieke Universiteit Leuven, Leuven, Belgium. Tau-4R and tau-P301L was expressed in neurons in the brain of transgenic mice and in the yeast Saccharomyces cerevisiae. Tau-4R was more phosphorylated than tau-P301L at three months of age in transgenic mice, but a fraction of tau became hyperphosphorylated only with age and onset of tauopathy. By contrast, a fraction of tau-4R became hyperphosphorylated in yeast as well, especially in a strain deficient in the yeast orthologue Pho85, while this fraction was not formed in a strain deficient in Mds1, the GSK-3â orthologue. This hyperphosphorylated form of tau (designated hP-tau) was mainly cytosolic in yeast but Sarkosylinsoluble in transgenic mice, while Sarkosyl-insoluble tau in yeast was phosphorylated at fewer sites than in brain of mice. Both hP-tau in yeast and in mice was conformationally altered, indicated by MC-1 reactivity. A comprehensive scheme for tau filament formation based on combined data of both models is presented. Phosphorylation by GSK-3ß is a first step for tau filament formation, causing and/or stabilising conformational change of tau, and promoting filament formation and additonal phosphorylations.  FULL TEXT |
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