S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila

Michelle L. Steinhilb, Dora Dias-Santagata, Erin E. Mulkearns, Joshua M. Shulman, Jacek Biernat, Eva Maria Mandelkow, Mel B. Feany

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


The microtubule-associated protein tau is hyperphosphorylated abnormally in AD and related neurodegenerative disorders. Many phospho epitopes created by proline directed kinases (SP/TP sites) show relative specificity for disease states. To test whether phosphorylation at the disease-associated SP/TP sites affects tau toxicity in vivo, we expressed a form of tau in Drosophila in which all SP/TP sites are mutated to alanine. We find that blocking phosphorylation at SP/TP motifs markedly reduces tau toxicity in vivo. Using phosphorylation- specific antibodies, we identify a positive correlation between increased phosphorylation at disease-associated sites and neurotoxicity. We use the phosphorylation-incompetent version of tau to show that kinase and phosphatase modifiers of tau neurotoxicity, including cdk5/p35, the JNK kinase hemipterous and PP2A act via SP/TP phosphorylation sites. We provide direct evidence in an animal model system to support the role of phosphorylation at SP/TP sites in playing a critical role in tau neurotoxicity.

Original languageEnglish
Pages (from-to)1271-1278
Number of pages8
JournalJournal of Neuroscience Research
Issue number6
StatePublished - May 1 2007


  • Alzheimer's disease
  • Kinase
  • Neurodegeneration
  • Phosphorylation
  • Tauopathy


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