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Vol. 18, Issue 12, 5060-5068, December 2007

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Tau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo

Michelle L. Steinhilb^*, Dora Dias-Santagata^,, Tudor A. Fulga^,, Daniel L. Felch, and Mel B. Feany

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and *Department of Biology, Central Michigan University, Mt. Pleasant, MI 48859

Submitted April 11, 2007; Revised August 22, 2007; Accepted October 2, 2007
Monitoring Editor: Erika Holzbaur

Tau is a microtubule binding protein implicated in a number of human neurodegenerative disorders, including Alzheimer's disease. Phosphorylation of serine-proline/threonine-proline sites, targeted by proline-directed kinases, coincides temporally with neurodegeneration in the human diseases. Recently, we demonstrated that this unique group of serines and threonines has a critical role in controlling tau toxicity in a Drosophila model of tauopathy. Here, we use a combination of genetic and biochemical approaches to examine these sites individually and to determine which of them is primarily responsible for controlling tau neurotoxicity. Despite the importance placed on individual phosphoepitopes and their contributions to disease pathogenesis, our results indicate that no single phosphorylation residue plays a dominant role in controlling tau toxicity. These findings suggest that serine-proline/threonine-proline sites cooperate to mediate neurodegeneration in vivo.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Mel B. Feany (mel_feany{at}hms.harvard.edu).

Abbreviations used: SP/TP, serine-proline/threonine-proline; TOR, target of rapamycin.

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