Title: Serine-409 phosphorylation and oxidative damage define aggregation of human protein tau in yeast
Authors: Vanhelmont, Thomas
Vandebroek, Tom
De Vos, Ann
Terwel, Dick
Lemaire, Katleen
Anandhakumar, Jayamani
Franssens, Vanessa
Swinnen, Erwin
Van Leuven, Freddy
Winderickx, Joris # ×
Issue Date: Jun-2010
Publisher: Published by Elsevier Science B.V. on behalf of the Federation of European Microbiological Societies
Series Title: FEMS Yeast Research vol:10 issue:8 pages:992-1005
Abstract: Abstract Unraveling the biochemical and genetic alterations that control the aggregation of protein tau is crucial to understand the etiology of tau-related neurodegenerative disorders. We expressed wild type and six clinical frontotemporal dementia with parkinsonism (FTDP) mutants of human protein tau in wild-type yeast cells and cells lacking Mds1 or Pho85, the respective orthologues of the tau kinases GSK3beta and cdk5. We compared tau phosphorylation with the levels of sarkosyl-insoluble tau (SinT), as a measure for tau aggregation. The deficiency of Pho85 enhanced significantly the phosphorylation of serine-409 (S409) in all tau mutants, which coincided with marked increases in SinT levels. FTDP mutants tau-P301L and tau-R406W were least phosphorylated at S409 and produced the lowest levels of SinT, indicating that S409 phosphorylation is a direct determinant for tau aggregation. This finding was substantiated by the synthetic tau-S409A mutant that failed to produce significant amounts of SinT, while its pseudophosphorylated counterpart tau-S409E yielded SinT levels higher than or comparable to wild-type tau. Furthermore, S409 phosphorylation reduced the binding of protein tau to preformed microtubules. The highest SinT levels were found in yeast cells subjected to oxidative stress and with mitochondrial dysfunction. Under these conditions, the aggregation of tau was enhanced although the protein is less phosphorylated, suggesting that additional mechanisms are involved. Our results validate yeast as a prime model to identify the genetic and biochemical factors that contribute to the pathophysiology of human tau.
ISSN: 1567-1356
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Physiology of Plants and Micro-organisms Section - miscellaneous
Laboratory for Functional Biology (-)
Gene Expression Unit
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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