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Title: Identification and isolation of a hyperphosphorylated, conformationally changed intermediate of human protein tau expressed in yeast
Authors: Vandebroek, Tom ×
Vanhelmont, Thomas
Terwel, Dirk
Borghgraef, Peter
Lemaire, Katleen
Snauwaert, Johan
Wera, Stefaan
Van Leuven, Freddy
Winderickx, Joris #
Issue Date: Aug-2005
Publisher: American Chemical Society
Series Title: Biochemistry vol:44 issue:34 pages:11466-11475
Abstract: Hyperphosphorylation and aggregation of protein tau are typical for neurodegenerative tauopathies, including Alzheimer's disease (AD). We demonstrate here that human tau expressed in yeast acquired pathological phosphoepitopes, assumed a pathological conformation, and formed aggregates. These processes were modulated by yeast kinases Mds1 and Pho85, orthologues of GSK-3beta and cdk5, respectively. Surprisingly, inactivation of Pho85 increased phosphorylation of tau-4R, concomitant with increased conformational change defined by antibody MC1 and a 40-fold increase in aggregation. Soluble protein tau, purified from yeast lacking PHO85, spontaneously and rapidly formed tau filaments in vitro. Further fractionation of tau by anion-exchange chromatography yielded a hyperphosphorylated monomeric subfraction, termed hP-tau/MC1, with slow electrophoretic mobility and enriched with all major epitopes, including MC1. Isolated hP-tau/MC1 vastly accelerated in vitro aggregation of wild-type tau-4R, demonstrating its functional capacity to initiate aggregation, as well as its structural stability. Combined, this novel yeast model recapitulates hyperphosphorylation, conformation, and aggregation of protein tau, provides insight in molecular changes crucial in tauopathies, offers a source for isolation of modified protein tau, and has potential for identification of modulating compounds and genes.
URI: 
ISSN: 0006-2960
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Biochemistry Section (Medicine) (-)
Chemistry - miscellaneous
Molecular Physiology of Plants and Micro-organisms Section - miscellaneous
Associated Laboratories - miscellaneous (-)
Laboratory for Functional Biology (-)
Gene Expression Unit
× corresponding author
# (joint) last author

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