Present addresses: Katleen Lemaire, Katholieke Universiteit Leuven, Afd. Biochemie, Herestraat 49-bus 901, BE-3000 Leuven, Belgium. Tom Vandebroek, Genzyme Flanders, 2440 Geel, Belgium. Dick Terwel, Klinische Neurowissenschaften, 53127 Bonn, Germany.
Serine-409 phosphorylation and oxidative damage define aggregation of human protein tau in yeast
Article first published online: 5 NOV 2010
© 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved
FEMS Yeast Research
Special Issue: Yeasts as a Model for Human Diseases
Volume 10, Issue 8, pages 992–1005, December 2010
How to Cite
Vanhelmont, T., Vandebroek, T., De Vos, A., Terwel, D., Lemaire, K., Anandhakumar, J., Franssens, V., Swinnen, E., Van Leuven, F. and Winderickx, J. (2010), Serine-409 phosphorylation and oxidative damage define aggregation of human protein tau in yeast. FEMS Yeast Research, 10: 992–1005. doi: 10.1111/j.1567-1364.2010.00662.x
Editor: Bruno Dumas
- Issue published online: 5 NOV 2010
- Article first published online: 5 NOV 2010
- Received 27 February 2010; revised 8 June 2010; accepted 16 June 2010.Final version published online 21 July 2010.
- oxidative stress;
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 GSK3β 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.